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  • Innovation in Medicinal Chemistry: Unlocking Unsolved Diseases

    By Juergen Mack, Vice-President, Medicinal Chemistry and 
    Darryl McConnell, Senior Vice President and Research Site Head, Austria

    Juergen Mack, Vice-President, Medicinal Chemistry and  Darryl McConnell, Senior Vice President and Research Site Head, Austria

    Recent innovation in medicinal chemistry has opened up avenues to discover medicines for diseases that we could not have imagined even just a few years ago. At Boehringer Ingelheim, we like to think of our medicinal chemists as molecular locksmiths, searching for ‘locks’ on the surface of proteins implicated in disease and designing drugs or molecular ‘keys’ to fit into these ‘locks’. The lock and key analogy, conceived by the German chemist Emil Fischer over 120 years ago, is still relevant but today’s diseases require medicinal chemists to discover much smarter keys - keys that do more than simply turning off a disease-causing protein. For example, today’s oncology drug molecules need to be highly selective and powerful at the same time while modern CNS drugs need to gently modulate brain activity.

    Taking structure-based drug design to the next level

    The strength of a drug’s action depends largely on how well it fits in the lock or binding site of the disease-causing protein. To design a perfectly fitting key we need to see, at the atomic level, what happens inside the lock once the key binds. That’s the principle behind structure-based drug design. Seeing, atom for atom, exactly how a potential drug candidate binds, which atoms fit perfectly and which ones do not, enables us to discover the precision quality molecules that are demanded of today’s most important drug targets.

    The rigorous application of structure-based drug design has enabled us to make important progress in discovering potential drugs for KRAS, one of the so-called undruggable targets in cancer called ‘cancer’s big four’. The challenge with KRAS is that its two ‘locks’ are very shallow and polar and, as such, are extremely difficult to find keys which fit tightly enough to be a potential drug. This is particularly frustrating because KRAS mutations occur in one in seven of all human cancers, making it the most frequently mutated oncogene which has remained undrugged since its discovery in 1982. Normally difficult projects such as KRAS are only able to obtain protein crystal structures for around 1 in 100 compounds. To finally make progress against KRAS, we took structure-based drug design to a new level and obtained three-dimensional “lock and key” structures for every single KRAS ligand that we synthesized in the laboratory on the way to a drug candidate.1 This led to a molecule called BI-2852, a KRAS inhibitor that binds with nanomolar affinity to the so-called switch I/II lock on KRAS and triggers antiproliferative effects in KRAS mutant cells.2

    Precision pictures for precision drug design

    Because of the transformational power of structure-based drug design we have become expert photographers in obtaining three-dimensional “lock and key” photographs. Unfortunately, obtaining such 3D pictures is not as simple as pressing the button on a smart phone. 
    There are three main approaches that can be used to “take” pictures for a broad range of proteins and protein assemblies.
    1. Nuclear Magnetic Resonance (NMR) spectroscopy is mainly used for very flexible proteins or protein domains in solution with a lower size limit
    2. X-ray crystallography uses near-to-perfect crystals of the disease-causing protein in a more static fashion by using X-ray diffraction mainly at very low temperature (100 K)
    3. Cryo-electron microscopy (cryo-EM) is a more recent approach which utilizes powerful microscopes also at very low temperature to determine 3D structures of proteins and large macromolecular protein assemblies in solution

    To obtain X-ray crystal structures you first need to obtain perfectly pure protein with the help of bacteria, yeast, insect or mammalian cells. Then using robotics, a cold room and patience we test thousands of conditions until we can grow an almost perfect crystal of the protein. Finally, it is bombarded with a beam of X-rays which locate the position of electrons. Computer algorithms convert these huge data sets into atom positions that lead to the final three-dimensional picture.

    X-ray crystallography works well for small or more rigid disease-causing proteins but it struggles with large flexible proteins and complexes containing multiple proteins. This is where the new kid on the block, cryo-electron microscopy excels. Cryo-EM takes 2D projections of the protein with an electron microscope that are reconstructed to a 3D model afterwards. No crystals have to be grown but the samples need to be meticulously prepared and then kept in a thin layer of non-crystalline ice cooled down to very low temperatures (100 K) with liquid nitrogen, or close to absolute zero, using liquid helium.

    The destruction approach to drug design

    A new class of drug molecules has been recently discovered that promises to significantly expand what is druggable. In contrast to classical drugs which turn off disease-causing proteins, this new class completely degrades proteins. These ‘destructors’ are PROTACS (Proteolysis Targeting Chimeras) that ‘hijack’ the cell’s natural disposal system to shred disease-causing proteins. Hijacking naturally occurring cellular systems to treat disease is a new and exciting way to design drug molecules and is being extended to concepts beyond degradation. To do this a “double key” is needed, one key to bind to the disease-causing protein and a second key to bind to the cellular system you want to hijack. In the case of PROTACs, proteins called ubiquitin ligases - enzymes that tag proteins for destruction by the cell’s proteasome - are hijacked.

    We used PROTACs to target SMARCA2, a protein that plays an important role in lung cancer. It is part of a large, almost indestructible complex, called the BAF complex, which has two known “locks”. With PROTACs it doesn’t matter which “lock” you choose, so we chose the easier lock located on the so-called bromodomain which led to the potent PROTAC compound ACBI1. ACBI1 is able to degrade SMARCA2 out of the BAF complex, akin to removing an individual brick out of wall, and effectively kills lung cancer cells in vitro.3

    Accelerating drug design with Artificial Intelligence

    The key fitting perfectly into its lock is just one of many criteria a drug molecule must fulfil. There are more than fifty parameters to be considered to successfully discover a new drug. This, combined with the enormous size of chemical space (~1060 molecules), requires an iterative endeavor which leverages the joint brain power of scientists working together as a team. At Boehringer Ingelheim we are convinced that recent developments in the fields of machine-learning and Artificial Intelligence (AI) can massively accelerate the exploration of chemical space and drug discovery as a whole.

    As a successful drug discovery organization with decades of experience, we have more than 300 million data points at our disposal. For every drug discovery project hundreds of data points are measured every week. To master the challenges of modern drug discovery, it is imperative to augment our creativity and scientific expertise with intelligent algorithms that constantly analyse data at large scale, draw conclusions and derive scientific hypotheses.

    In the past, medicinal chemists designed, synthesized and tested a few thousand molecules, largely sequentially, to fully assess the potential of each molecule. Digital tools and AI have the potential to transform this process. Using AI we generate millions of molecules virtually and predict their molecular properties using computer algorithms to choose the best molecules to synthesize in the laboratory. It’s like using a navigation system for chemical space to rapidly weigh up different options on which route to take to get to the desired destination in the shortest time.

    Our brains also function according to the lock and key principle. Naturally occurring molecules called neurotransmitters, are the keys which fit into locks on neurons to transmit signals. In contrast to oncology where we need powerful molecules that selectively target cancer cells and destroy them, for diseases affecting the central nervous system such as schizophrenia we need more subtle “keys” that are able to selectively modulate brain function. One such class of drugs are negative allosteric modulators (NAM). NAMs are a second key which bind to a different lock at the same time as the naturally occurring neurotransmitter and dampen its effect. Efficient NAMs are extremely difficult to design but with the support of AI we were able to design a NAM for the GABA α5 receptor much faster and in only a few iterations.4 GABA α5 is a key protein involved in a wide range of essential processes in the brain including schizophrenia. Our AI algorithms helped us to filter 200,000 virtual compounds down to 200 compounds that most closely matched the required criteria. The accuracy was so good and the predictability so high that we were able to go straight to advanced stages of profiling to identify two drug candidates. With the support of AI this took less than four months, less than half the time of using traditional methods.

    Leveraging technologies to innovate for patients

    Pushing back the boundaries with new technologies in medicinal chemistry is enabling us to find molecules for targets that previously seemed undruggable with traditional approaches. And this is just the start. Approaches such as structure-based drug design, PROTACS and AI are enabling us to effectively explore the infinite possibilities of chemical space: Locating the right place to start and then guiding medicinal chemists on which direction to take to discover innovative drugs that improve patients’ lives.


    1. Kessler, D., Bergner, A., Böttcher, J., Fischer, G., Döbel, S., Hinkel, M., Müllauer, B., Weiss-Puxbaum, A. and McConnell, D.B., 2020. Drugging all RAS isoforms with one pocket. Future Medicinal Chemistry, (0).
    2. Kessler, D., Gmachl, M., Mantoulidis, A. et al. Drugging an undruggable pocket on KRAS. PNAS 2019; 116: 15823-15829
    3. Farnaby, A., Koegl, M., Roy M.J. et al. BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design. Nat Chem Biol 2019; 15: 672-680
    4. Hucke, O., Bieler, M., Larsen, J., Dyhring, T., Jacobsen, T., Nielsen, K., Schauerte, H., Cui, Y., Peters, S., Heine, N., Eickmeier, C., Arban, R. and Montel, F.,2019, August. Leveraging machine learning and the Free-Wilson approach in lead optimization: Efficient discovery of a new chemical class modulating the GABAA alpha 5 receptor. In Abstracts of Papers of the American Chemical Society (Vol. 258). 1155.
  • Leading the science – Taking Cancer On With Smart Combinations

    Norbert Kraut, Ph.D., Global Head of Cancer Research, Boehringer Ingelheim

    Developing smart combinations of cancer cell-directed therapies that hit cancer cells at the molecular target initiating and driving their growth, with therapies selected rationally to boost anti-cancer activity and limit resistance, is central to our research strategy to optimize the treatment of cancers where there is the greatest unmet need for patients.

    Despite significant progress over recent decades, many key molecular drivers for a wide range of cancers remain undruggable. Only 10-15% of cancer patients currently benefit from drug treatment targeting the genomic aberrations driving their cancer. Our mission is to change this. We’re taking cancer on by working on pioneering approaches to identify key cancer cell dependencies that drive the growth and proliferation of cancer cells. Our scientists are developing novel therapies to turn these drivers off, and combining them with specially selected partners to switch off multiple drivers, as well as with immunotherapy to harness the patient’s immune system to fight cancer cells.

    Finding smart combinations to tackle ‘undruggable’ targets

    We’re digging deep into the science and taking a precision approach to develop smart combinations to bring the greatest benefit to patients.

    The first step is to find cancer-cell directed therapies that induce rapid tumor shrinkage. But we know that the long-term efficacy of current targeted therapies has been limited by the development of resistance, leading to relapse and disease progression. Cancer cells quickly find ways to circumvent the effects of targeted drugs by mutating or re-routing along alternative pathways. So we’re using a smart science approach to understand molecular pathways at a deep level to identify the ‘Achilles heels’ where we can potentially outwit the cancer cells at the same time as finding innovative ways to increase and prolong anti-cancer effects with combination partners.

    Immune therapies often take longer to act than cancer cell-directed therapies but can achieve much more long-lasting responses. So part of our smart combination strategy is exploring how to transform ‘cold’ tumors, which have no, or limited, immune system activity, making them unresponsive to immuno-therapy, into ‘hot’ tumors so that the patient’s immune system can be recruited to fight cancer with immuno-oncology therapies. By combining both approaches, patients gain the immediate benefit and high responses of cancer-cell targeted therapies and the longer-term survival benefit of immunotherapy.


    KRAS is one of the front-line sensors that triggers activation of a chain of signalling molecules connecting the cell surface to the nucleus to control normal cell growth, survival and differentiation. Its central role in cell signalling in a range of common cancers plus its heart-shaped structure means it is known as ‘the beating heart of cancer’. Blocking KRAS has huge potential for benefiting many cancer patients. But discovering and developing effective therapies directed against this key cancer target has proved challenging. We believe that blocking multiple KRAS mutant variants simultaneously is a highly attractive therapeutic strategy to tackle cancers harboring KRAS-driver mutations.

    Working on smart combination approaches directed at KRAS, we use our signalling expertise to understand at a systems level what happens when a tumor is treated with a KRAS-targeted compound, unravelling how the tumor finds ways to adapt. Understanding the adaptation mechanisms informs our strategy to develop the ideal combination partners. There is a broad range of intrinsic and adaptive mechanisms of resistance depending on the cancer type, the type of KRAS mutation, the mutational landscape of co-mutations in individual cancers and the type of KRAS inhibitor. We are studying the conditions under which cancer cells, driven by newly emerging KRAS mutations, become prominent resulting in relapse. This makes a pan-KRAS inhibitor a rational approach. We also know that the KRAS signalling pathway can become re-activated at multiple key nodes. So understanding at which levels of the pathway to intersect in a vertical way most effectively becomes an imperative. Finally, parallel signalling pathways can also become activated, thereby requiring combination partners that achieve most profound effects by horizontal pathway blockade.

    Our smart science approach is enabling us to lead the way in exploring a pan-KRAS approach and this has resulted in the development of our first-in-class SOS1::KRAS inhibitor BI 1701963. It is a protein-protein inhibitor that binds to SOS1 (Son of sevenless homolog 1), one of the guanine nucleotide exchange factors that switches KRAS to the ‘on’ state to signal cell proliferation. Inhibiting SOS1 limits downstream signalling pathways that control proliferation and survival of cells and antagonizes the rebound effect, a negative feedback relief induced by RAF/MEK/ERK pathway inhibitors.

    We found that vertical pathway inhibition, combining a SOS1 inhibitor with a MEK inhibitor, achieves even more profound blockade of KRAS signalling and durable tumor regression in models of KRAS-driven cancers. So we are currently investigating BI 1701963 as monotherapy and in combination with the MEK inhibitor trametinib in phase 1 trials in patients with KRAS mutation-positive solid tumors. We are also planning to initiate clinical trials with our own investigational MEK inhibitor, BI 3011441, in combination with BI 1701963 in 2021.

    Looking to explore this potentially potent pairing even further, our clinical collaboration with Mirati Therapeutics will evaluate BI 1701963 with MRTX849 – a KRAS G12C selective inhibitor. Preclinical data suggest that the combination of a KRAS G12C inhibitor with a SOS1::pan-KRAS inhibitor results in increased anti-tumor activity based on their complementary mechanisms. By shifting the equilibrium from active KRAS(ON) towards the inactive KRAS(OFF) form, SOS1::pan-KRAS inhibitors have the potential to sensitize KRAS G12C mutant tumors to covalent KRAS G12C inhibitors that bind to KRAS(OFF) – possibly increasing the therapeutic benefit for patients with lung and colorectal cancers.

    In addition, the non-overlapping mechanisms of resistance when combining a KRAS inhibitor with an immuno-oncology agent has huge potential to boost the duration of treatment response. We are exploring this by teasing out what happens when KRAS-directed inhibitors induce a pro-inflammatory tumor microenvironment. This results in an increased number of tumor infiltrating lymphocytes, with the potential to stimulate the immune response, and provides a rationale to combine with immune-oncology therapies such as PD-1 inhibitors. This offers the intriguing possibility of turning ‘cold’ tumors such as colorectal and pancreatic cancer ‘hot’ with the targeted treatment so they become responsive to immunotherapy.

    We are also exploring a prime boost vaccine targeting KRAS, with potential for synergies with small molecular KRAS inhibitors. This could boost long-term, immune-mediated control of tumor growth in patients with KRAS-driven tumors. And we don’t stop there as we continue to pursue potential new immuno-oncology combinations by unravelling the additional direct effects of KRAS inhibitors on tumor, stromal and immune cells.


    Aberrant activation of Wnt/beta-catenin signalling is common in the onset and progression of several cancers. Beta-catenin is mutated or the upstream regulator APC is inactivated in almost all colorectal cancers. It also helps cancer cells to evade the immune system, including immune activation prompted by immuno-oncology therapies. The exciting potential of this dual role in cancer is that inhibiting Wnt/beta-catenin signalling could directly impair cancer cell growth at the same time as making cancer cells more vulnerable to immuno-oncology drugs.

    Our team is leading the science with the first potent inhibitor targeting a critical node of the Wnt/beta-catenin pathway. The LRP5/6 antagonist BI 905677 has been developed from our comprehensive characterization of the Wnt/beta-catenin pathway and our expertise in precision biologics. It simultaneously binds to two separate antigen-recognition sites – the Wnt1 and Wnt3a epitopes – of closely related proteins that span the cell membrane, the lipoprotein receptor-related proteins (LRPs) LRP5 and LRP6.   
    By binding these epitopes BI 905677 blocks the formation of a Wnt complex that would normally trigger accumulation of beta-catenin, resulting in anti-tumor as well as immune-stimulating effects.

    What’s very exciting about combining an LRP5/6 inhibitor with immuno-oncology drugs is that the combination approach is based on inhibiting a pathway that leads to a profound impact on cancer cells at the same time as boosting the immune system and making ‘cold’ tumors ‘hot’. This could apply in a wide range of cancers where the wnt/beta-catenin pathway is active and preventing the immune system from functioning.

    The future is looking bright

    Our precision approach to developing smart combinations is bearing fruit, with several innovative approaches already in clinical trials. We are on the way to our goal of transforming the lives for the millions of cancer patients who currently have no effective therapies. That’s the key driver for what we do and it’s why this is a challenge we are going to win by understanding the biology and complexity of cancers and developing the smartest combinations.

  • Bringing our Best to the Fight Against COVID-19

    by Michel Pairet, Member of the Board of Managing Directors, Innovation (left) and Clive R. Wood, Global Head of Discovery Research (right), Boehringer Ingelheim

    As the world grapples with the challenge of another potentially more deadly upsurge in COVID-19 infections, we at Boehringer Ingelheim, along with the rest of the global scientific community, are digging deep into our knowledge and pipeline to find new options to combat this disease. Every statistic has a human story associated with it and it is this, together with our scientists’ deep commitment to rapidly find effective treatments to fight this devastating disease, that compels us to do everything we can to help patients who are suffering and relieve pressure on healthcare systems around the world.

    Searching for opportunities to help the most severely affected

    In January, we began learning – along with the rest of the scientific world – about the pathology and course of COVID-19 infections. Our scientists have benefited from the unprecedented spirit of global collaboration among the scientific community. And our own extensive experience in respiratory and cardiovascular diseases, combined with knowledge gathered through exploration of infectious disease therapy approaches, has allowed us to rapidly identify mechanisms that could be helpful in the fight against this global menace.

    By March, and leaving no stone unturned, our scientists had identified a targeted therapeutic approach (from work in an unrelated disease area) with a mechanism found to play a potentially key role in the onset of one of the most severe hallmarks of COVID-19 – Acute Respiratory Distress Syndrome (ARDS).  Given the potential value to patients and being, to the best of our knowledge, the only team to have a clinical-stage agent targeting this pathway, we knew we had to act. Now, just a few months on from those early days of research, BI 764198, an inhibitor of TRPC6, a non-selective receptor-operated cation channel, is entering a phase II clinical trial.

    BI 764198 is a novel, first-in-class compound that could potentially tackle life-threatening complications of COVID-19. Our TRPC6 inhibitor has shown preclinically the potential to stop the influx of fluid into the lungs which causes pulmonary edema and leads to ARDS. This represents a potentially important intervention for patients admitted to hospital with COVID-19 to stop their progression to, or reduce the severity of pulmonary edema, and reducing the need for intensive care treatment and/or supported ventilation.

    This is the first phase in an accelerated clinical development program which could see this potential new medicine begin phase 3 trials in a larger group of patients in early 2021 with the earliest approval expected later next year.

    Addressing the challenge of life-threatening respiratory symptoms

    Acute respiratory distress syndrome is a severe lung condition that occurs when fluid builds up in the small air sacs (alveoli) in the lungs. The fluid stops the lungs from filling with air, which means less oxygen reaches the bloodstream and deprives the essential organs of the oxygen they need to function.

    With no currently approved treatments available for ARDS, there is significant unmet patient need. One third of patients hospitalized with COVID-19 develop acute respiratory distress syndrome.1 These are some of the most severely ill patients in hospitals, many of whom will require intensive care treatment and supported ventilation.

    How TRPC6 inhibition could fit into the COVID19 treatment regimen

    Standing together with the scientific community to do all we can

    We stand shoulder-to-shoulder with our colleagues in the biomedical community around the world who are doing everything they can and using all their expertise to bring forward new treatments and vaccines to help patients who are suffering from the effects of COVID-19. And while the approval of a safe and effective vaccine will be a pivotal moment in our fight against COVID, pushing back the pandemic through the widespread immunization of the global population will take time. There will also be many patients – particularly the elderly and more vulnerable – who may have a relatively poor response to a vaccine, and who may need effective therapeutic treatments.

    Alongside the rest of the world, we hope that every clinical trial is a success, providing vaccines and treatments that will rid the world of this virus or lessen its burden on those infected. In the meantime, we will continue to strive to be first4patients working around the clock until the fight against COVID-19 is won.


    1 Tzotzos et al. Critical Care (2020) 24:516

  • Disentangling fibrosis: finding ways to fix ‘repair gone wrong’

    by Carine Boustany  US Executive Director Cardiometabolic Diseases Research, Boehringer Ingelheim

    Carine Boustany, US Executive Director Cardiometabolic Diseases Research, Boehringer Ingelheim

    Millions of patients around the world are suffering from the dramatic effects of fibrotic diseases; their lives forever changed by the damage fibrosis inflicted to their organs. As a researcher, I am inspired by their stories. Now, more than ever, I am convinced that we can change their disease trajectory, reverse or halt the worsening of fibrosis, and by doing so save or improve their lives. 

    Whether the damage occurs in the liver, as in non-alcoholic steatohepatitis (NASH); in the lung, as in idiopathic pulmonary fibrosis (IPF); in the kidney, as in chronic kidney disease (CKD); in the skin, as in scleroderma; or in the gut, as in inflammatory bowel disease (IBD); the consequences of fibrosis are devastating to patients’ health, and may ultimately necessitate drastic measures such as organ transplant, or tragically, cause an untimely death.

    The associated health care costs are substantial, reflecting the toll of fibrotic diseases on patients and society. Notably, a US Medicare study of beneficiaries aged 65 and older estimated annual total costs of IPF to the US healthcare system to be $2 billion, excluding medication costs.1 Similarly, lifetime costs associated with NASH are estimated to have reached $222 billion in 2017 in the USA, and incidence of new cases are predicted to continue to grow resulting in an estimated $359 billion lifetime costs by 2060.2


    Understanding what goes wrong

    Fibrosis has been, for some time, a key focus of drug discovery. There have been numerous attempts over the years to develop robust anti-fibrotic medicines, but the complexity of this pathogenesis has led to several clinical failures. Consequently, to date, there are only two approved anti-fibrotic medicines available to patients.

    Over the past years, we have come to understand that fibrosis is essentially ‘repair gone wrong’. In healthy tissue, an insult or injury triggers a complex cascade of cellular and molecular responses that ultimately repair the damage or heal the wound. In contrast, in the disease state, a chronic insult leads to a disruption of the homeostatic balance between injury and repair. The repair mechanism goes into overdrive resulting in excessive connective tissue deposition, often accompanied with chronic inflammation, and ultimately leading to a remodeling of the organ and loss of its functionality. Our challenge in fibrosis research is to restore the lost homeostatic balance by blocking excessive matrix accumulation while allowing healthy repair to take place.

    Building on success with nintedanib

    We made a significant advance in the treatment of lung fibrosis with the discovery and development of OFEV® (nintedanib), the first treatment approved by the FDA for IPF (2014), subsequently approved for systemic sclerosis-associated interstitial lung disease (2019), and in March of this year for the treatment of chronic interstitial lung disease with a progressive phenotype. Discovering nintedanib has enabled us to gain insights into the pathways critical in lung fibrosis and gauge the translatability of our preclinical models in a new way. Further, by comparing its effects across fibrotic organs, we are able to assess the importance of specific fibrotic pathways in different diseases. Nintedanib gives us a unique opportunity to learn from clinical translational research and apply these findings to the discovery of novel anti-fibrotics.

    Excessive deposition of extracellular matrix in the interstitium creates fibrotic scar tissue

    Taking a dual approach to boost success

    Using this expertise and experience, we are exploring shared pathways across multiple fibrotic diseases. In the long term, this will enable us to advance the most effective anti-fibrotic medicines and provide them to patients with a range of fibrotic diseases such as NASH, IPF, IBD, and scleroderma. However, we are cognizant that each of these diseases have tissue and disease-specific aspects beyond fibrosis. Our comprehensive research programs in these areas allow us to design and test specific combinations that will give the greatest benefit for patients. For example, in the case of NASH, a combination of an anti-fibrotic with an anti-steatotic, may not only reverse the fibrosis, but also block the insult leading to the injury.

    Honing in on the IL-11 pathway

    In our quest for transformative therapies, we are exploring innovative mechanisms, differentiated from previously explored anti-fibrotic approaches. In particular, the interleukin-11 (IL-11) pathway is emerging as a promising therapeutic target for treating fibrotic diseases. The IL-11 cytokine acts on key cell types involved in fibrosis; it drives fibroblast activation required for the synthesis of fibrogenic proteins and injures the epithelium leading to further organ damage. One of the key advantages of targeting the IL-11 pathway is its propensity to causing fibrosis in multiple organs including the lung, liver, skin, gut, kidney and heart.3,4 Laboratory studies have also shown that anti-IL-11 treatment has the potential to stop – and even reverse fibrosis – in different fibrotic diseases.5,6

    We recently announced a partnership with Enleofen, adding the biotech company’s world- leading preclinical anti-IL11 platform to our existing expertise and pipeline portfolio. This expands our broad panel of research collaborations in these areas, including projects to explore novel pathways and molecular targets for the treatment of IPF and NASH with the Harvard Fibrosis Network. Working with our partners, we are unraveling the molecular underpinning of fibrosis and are advancing a growing pipeline of diverse and innovative mechanisms with the potential to transform the treatment of fibrotic diseases.

    Image courtesy of Enleofen Bio Pte Ltd.

    Working together to beat fibrosis

    In addition to tapping into the knowledge and skills of our partners, we recognize the need to leverage expertise across R&D and other areas such as translational clinical medicine, by facilitating cross-functional and global working. Our large community of scientists with diverse expertise and disease knowledge – we call them our ‘fibrosis cluster’ – work together to identify shared mechanisms and pathways which could point to the most effective anti-fibrotic medicines and to the fastest approach for demonstrating their action in the clinic. We are convinced that this multi-disciplinary approach is the key to unlocking the biology that will lead to transformative treatments for patients.

    As a drug discoverer, I aspire to improve the lives of patients; patients with IPF who struggle to breath, patients with liver cirrhosis with no option but liver transplant, patients with scleroderma suffering from painful and fragile skin, and patients with many other devastating conditions. Effective anti-fibrotic therapies can truly transform their lives, and together with my colleagues at Boehringer Ingelheim, I am committed to the discovery of these breakthrough medicines.






    1. Collard H et al. Ann Am Thorac Soc 2015;12(7):981–987
    2. Younossi Z et al. Hepatology 2019; 69(2):564-572
    3. Schafer S et al. Nature 2017 December 07; 552(7683)
    4. Cook S and Schafer S. Annu. Rev. Med. 2020;71:263–76
    5. Ng et al., Sci. Transl. Med. 11, eaaw1237 (2019)
    6. Widjaja A et al. Gastroenterology 2019;157:777–792

    NEW opn2EXPERTS program seeks scientific expertise to address important questions in fibrosis

    With its new opn2EXPERTS program, Boehringer Ingelheim addresses important biologic topics on with relevance to human disease.

    We seek scientific expertise to solve important biologic questions together to advance science in novel directions for the benefits of patients in need. In exchange, we are open for collaboration. Discover our most recent questions on the subject of fibrosis on below.

    • How would you propose identifying the role of exosomes in the onset and progression of IBD, SSc, and ILD?
    • How would you improve the understanding of the role of endothelial cells in the progression of SSc using novel cellular systems?


  • The View from Both Sides of the Table

    The View from Both Sides of the Table

    In brief: Scott DeWire is the US Head of Business Development & Licensing for Boehringer Ingelheim. In this article, Scott shares stories from his career journey, which weave a path through science and business and have taught him first-hand the foundations of successful partnerships.  He reflects on how these experiences shape Boehringer Ingelheim’s Business Development & Licensing efforts.

    In any relationship, the ability to imagine yourself in the shoes of the other party is an invaluable skill.  Nowhere has this been more evident to me than in the job I’ve held for the last four years – in pharmaceutical partnering and business development. While common understanding and empathy aren’t always the first traits that come to mind when you think of a professional contract negotiator, these are indeed the lessons I continue to draw on to form successful partnerships. My own career path has been an amazing and somewhat accidental journey through both science and business, and it continues to teach me these valuable lessons in perspective over and over again.

    Scott DeWire Ph.D.
    US Head of Business Development & Licensing

    Scott DeWire Ph.D.  US Head of Business Development & Licensing

    I was recently asked a fairly standard question about how I got interested in a career in science. I admit, I always cringe a little when I answer this because the truth sounds made up. The summer I was 12 years old, I read Michael Crichton’s Jurassic Park. It was a sci-fi novel filled with the promises of molecular engineering with real life applications.  I recall being so excited that I put the book down and told my dad I had just figured out exactly what I was going to do with my life (although, I don’t think he took it very seriously at the time). These ideas lit the initial scientific spark in me and set me on a path to becoming a molecular biologist. 

    About 15 years later, after an undergrad in cell biology at the University of Connecticut and a brief stint as a lab technician at a major pharma company, I was wrapping up a PhD at the University of North Carolina. I decided the only place I wanted to do my postdoc was with Robert Lefkowitz at Duke. Lefkowitz was well known for his contributions to the discovery of G-protein-coupled receptors (for which he would later win the Nobel Prize in 2012). However, within a few hours of emailing my application package to Duke, I was summarily rejected.

    This initial failed attempt proved to be a critical juncture in my early career and offered me my first major lesson in perspective. After some encouragement from my PhD advisor, I decided to try again with Lefkowitz, and wrote him a letter explaining all the reasons it made sense to give me an interview. I approached it very pragmatically: my interview wouldn’t require him to pay any travel costs, nor did I need a lunch, and I explained that if after 15 minutes or so he felt his initial assessment was correct, he could dismiss me straight away without any reservations. Seeing the situation through his eyes, and showing him how he had almost nothing to lose by taking a chance on me must have made the difference, as Lefkowitz agreed to invite me for a full interview, and ultimately offered me the postdoc position.

    My time in the Lefkowitz Lab was particularly exciting, not just for the tremendous pace of discovery and chance to rub shoulders with some of the world’s best scientists, but also because it was there that I met life-long friends I would eventually co-found a biotech company, Trevena, with. Building this company, starting from just three guys with an idea and a grant, was a great experience that I reflect on frequently in my current role. I vividly recall feelings of uncertainty like “will we ever get funded?” while dealing with the rejection and criticisms from so many VC firms.  And later, once we were off the ground, the relentless pressure of hitting tranche-releasing milestones and the constant cycle of board meeting preparations. 

    I see these pressures in the forefront of entrepreneurs’ minds, and I can relate to what they are going through. Later, Trevena’s board would require us to secure a big pharma partnership as validation of our platform, and I got my first taste of business development, from the sell-side.  These experiences were foundational to understanding what potential partners are thinking when I meet them in my current role. Another thing that stays with me from my time at a biotech was how invigorating it was. Small companies, so dedicated to a singular hypothesis, must be zealous in pursuit of an idea. When I meet potential partners now, I love to see this same energy, passion, and excitement for science in their eyes.  For me to believe it, they have to believe it. 

    About five years later, I decided to join a large pharma company, Boehringer Ingelheim, because I wanted to experience the other side of the table. It’s been a fascinating experience to simultaneously understand what the biotech may be going through and also opened my eyes to a whole new set of concerns the large partner faces that I never realized during my biotech days. I admit, I underestimated how the pharma BD person really is the champion of the small company, aligning and gaining support within that large organization. So now I try to make this point when we enter term sheet discussions with new partners.

    Earlier this year, I started my new role as Executive Director, Head of Business Development & Licensing (BD&L), USA at Boehringer Ingelheim. I see it as my team’s duty to help bring the best scientific minds together to develop innovative medicines, so we can achieve the ultimate goal, which is to help patients.

    As a private company, we’re able to approach partnering differently. One of my favorite parts of my job is something we call Boehringer Ingelheim’s Grass Roots Initiatives.  This is a three-part program where it’s our goal to connect with and help grow local biotech ecosystems, including:  

    1. “Office Hours” which is a 1:1 small company mentoring program
    2. “BI academy” which is a series of informative panel discussions we host on topics of relevance to budding entrepreneurs, and
    3. “BI’s Innovation Prize” which is essentially a poster and pitch contest to win funding for lab space at a local incubator we sponsor. 

    We do these programs several times a year in major U.S. biotech hubs and recently expanded the program globally to Europe and Asia.  I always enjoy meeting young companies and hearing their stories at these events, and I think back to my time as a startup founder and how valuable this would have been for me to have access to something like this back then.

    Often at one of our Grass Roots events, an entrepreneur will ask me for the best advice that I can give to them.  I always say the same thing:  Focus on what it is that you do better than anybody else. Don’t try to do it all. Just figure out what your secret sauce is, what’s your value proposition, and then put all your effort there. If you can clearly define that, then please get in touch with me and we can talk further about partnering to develop the next generation of breakthrough medicines.

    If you’d like to hear more from the Boehringer Ingelheim BD&L team and the Boehringer Ingelheim External Innovation Hub about how we approach partnering for innovation in a post-pandemic world, please join us for an Endpoints Webinar panel discussion, “Perspectives on Partnering Post-Pandemic” on Wednesday, June 10, 2020 from 11:00 am – 12:00 pm EDT. Register here.

    Hope to virtually see you there!


  • Defeating COVID-19: the race we will win together

    by Michel Pairet, Member of the Board of Managing Directors, Innovation (left) and Clive R. Wood, Global Head of Discovery Research (right), Boehringer Ingelheim

    Michel Pairet, Member of the Board of Managing Directors, Innovation and Clive R. Wood, Global Head of Discovery Research, Boehringer Ingelheim

    We are all in a race to find solutions to halt the catastrophic toll on human health and wellbeing that COVID-19 is exacting. Two things will ensure success in fighting this pandemic: first, we are all standing together in open collaboration for common cause; and second, we will succeed because of science.

    It is alarming how much misery and havoc that the 29,903 ribonucleotide bases of SARS-CoV-2 have inflicted upon the world. However, no pandemic threat has previously faced the combined intellect and technology of 21st century science, with lines of communication powered by the internet and rapid research publications open to all. Humanity and its scientific community are united in a way that is unprecedented in our lifetimes. And we are using all our scientific capabilities and committing them in an international spirit of open science on a scale that has never been seen before.

    How can we re-direct existing products and drug candidates to combat SARS-CoV-2?

    As early as mid-January we started to consider how Boehringer Ingelheim could best help. We started to work on two key questions:

    We reviewed our clinical and preclinical pipelines.  We asked whether we may have compounds that could work directly against the virus, or compounds that might ameliorate the course of the disease in the most severely affected patients. This included using our extensive background in respiratory and cardiovascular diseases. As of today, we are investigating a number of potential opportunities that include:

    • Our tissue plasminogen activator alteplase (Actilyse®), following case reports suggesting potential to block hypercoagulation and prevent organ failure in severely ill COVID-19 patients.

    • Direct-acting antiviral small molecule compounds from previous virology projects, such as polymerase and protease inhibitors from our legacy HIV and HCV research.

    • The potential of our Inflammation and Cardiometabolic Diseases portfolio, including preclinical and early clinical stage drug candidates to address the hyperinflammation and epithelial/vasculature pathologies.

    How can we discover new drugs that combat SARS-CoV-2?

    Our scientists are using four platforms to generate monoclonal antibodies against the SARS-CoV-2 spike protein: human antibody phage display; immunized human antibody transgenic mice; antibodies isolated from the blood of people who have recovered from infection; and computational structure-based antibody design. It is already paying off: we have identified first candidates and partner laboratories are testing them for viral neutralizing effects.

    In parallel to our work on antibodies, we are using all of our expertise in medicinal chemistry and chemical assets to find small molecule inhibitors. We are screening our entire molecular library of more than one million compounds to identify those with potential activity to treat COVID-19. Our teams are using computational screening to speedily search this huge resource, starting with two priority viral targets: SARS-CoV-2 main protease and SARS-CoV-2 papain-like protease.1 The expertise we have built in artificial intelligence-aided optimization of drug candidates will speed our path.

    As important as identifying the best therapeutic candidates will be how quickly we can go from discovery to clinical testing. Our plans are advanced to do this at a record-breaking pace.

    Joining forces in new collaborations

    Boehringer Ingelheim researchers are active members of innovative collaborative approaches bringing together world-leading scientists from across the world, including:

    • A fast-track call initiated by the Innovative Medicines Initiative (IMI) of the European Union, bringing together industry and academic researchers to develop existing or new treatments to respond rapidly to COVID-19.2

    • The COVID-19 Therapeutics Accelerator launched by the Bill & Melinda Gates Foundation in a unique collaboration across the life sciences industry to help address this global health emergency and prepare for future public health challenges.3

    These partnerships are moving very rapidly with an unprecedented spirit of co-operation to push the boundaries of biomedical progress.

    Science serving society
    We are starting to make progress in the fight against COVID-19 although there will inevitably be twists and turns ahead. However, we are confident that biomedical science and our industry will succeed in playing a critical part in defeating this menace. It is an opportunity for the power of open science and collaboration to shine in the service of society. The race is on and we know it is a race we will win together.


    1. Zhang L, Lin D, Sun X et al. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. 
    2. IMI launches EUR45m call for proposals on the coronavirus. 3 March 2020.
    3. Bill & Melinda Gates Foundation. Life sciences companies commit expertise and assets to the fight against COVID-19 pandemic alongside Bill & Melinda Gates Foundation. 25 March 2020.
  • Enhanced gamma H2AX levels, a marker for DNA double strand breaks, were observed in the SOS1i + Irinotecan treated group compared to monotherapy of Irinotecan

    Fighting negative KRAS feedback  

    Marco Hofmann, Project Leader and Research Laboratory Head, Boehringer-Ingelheim Regional Centre, Vienna, Austria



    Almost all pancreatic cancers have KRAS mutations and more than 40 percent of colorectal cancers and over 30 percent of lung adenocarcinomas are driven by KRAS. There is a high unmet medical need as no drugs targeting KRAS have been approved to date. While promising clinical data were recently reported for covalent KRASG12C inhibitors, these compounds only address KRASG12C mutations. The task that we are committed to is enormous: directly targeting KRAS, blocking feedback and ultimately getting ahead of resistance. This is why our team has opted, amongst other approaches, to investigate pan-KRAS inhibition in conjunction with combination strategies that address a broad range of KRAS mutations and at that same time limit negative feedback.

    In contrast to KRASG12C inhibitors, our SOS1 inhibitors block the interaction of SOS1 with the inactive form of KRAS in a manner that is independent of KRAS mutation status. Our SOS1 inhibitor BI 1701963 has a broad activity against G12 and G13 mutant KRAS alleles, including the most prevalent G12C, G12D and G12V oncogenic variants. By selectively inhibiting SOS1, one of the two types of SOS, we are simultaneously slowing KRAS beating and blocking feedback. With feedback blocked, we are now able to permanently limit KRAS signaling by combining SOS1 inhibitors with inhibitors of other key proteins in the RAS signalling pathway, such as MEK.

    We have now confirmed that combining SOS1::KRAS inhibition by BI 1701963 with the MEK inhibitor trametinib has the potential to achieve tumor stasis or regression in vivo in a broad range of KRAS G12/G13 mut+ models tested. We also investigated the combination with irinotecan, a standard of care  in colorectal carcinoma, and could show that SOS1::KRAS inhibition with BI 1701963 augments the DNA damage and apoptosis caused by irinotecan. This further broadens the panel of combination partners for developing pan-KRAS  therapy regimens with BI 1701963. I am personally really excited to be able to further advance this compound with the aim of achieving our goal of delivering new breakthrough medicines for the many cancer patients, who have no viable therapy options to date.

    A Phase I clinical trial started end of 2019 (NCT04111458) to evaluate, safety, tolerability, pharmacokinetic and pharmacodynamics properties, and efficacy of BI 1701963 alone and in combination with Trametinib in patients with different types of KRAS mutant advanced solid cancers.

  • Darryl McConnell, Boehringer Ingelheim Cancer Research Site Head, Vienna, Austria

    Taking KRAS cancers on

    “Cancer starts within our cells where you can’t see anything with the naked eye“ – This is why Darryl McConnell, Ph.D., Research Site Head at Boehringer Ingelheim Regional Centre in Vienna, Austria draws analogies. Watch the full KRAS story to learn how we aim to drug all forms of KRAS and how we work on blocking negative feedback loops.

  • KRAS

    The Beginning of the End for KRAS Cancers

    Darryl McConnell, Research Site Head, Boehringer-Ingelheim Regional Centre, Vienna, Austria

    Darryl McConnell

    KRAS, or Kirsten RAt Sarcoma viral oncogene in full, was first identified as a key oncogene in 1982. We now know that it is the most important driver of cancer, with one in seven tumors driven by KRAS mutations, making it, in many ways the ‘holy grail’ for targeted cancer therapy. Almost all pancreatic cancers have KRAS mutations and more than 40 percent of colorectal cancers and over 30 percent of lung adenocarcinomas are driven by KRAS.

    The KRAS protein is a central node in one of the most important signalling networks within our cells. Known as ‘the beating heart of cancer’, it beats between two states: mostly ‘off’ in healthy cells and switching to ‘on’ in cancer cells. The challenge with finding effective treatments for KRAS-driven cancers is three-fold: not only do we need to find a way to switch KRAS off but we also need to keep it switched off and avoid the emergence of resistance. As yet, there are no drugs approved against RAS proteins, of which KRAS is the most important member.

    What really inspired me and the whole Boehringer Ingelheim oncology team to take KRAS on was the sheer numbers of cancer patients that could benefit if we succeeded. Drugging KRAS is first and foremost a chemistry problem. As a chemist, I couldn’t accept that KRAS was an unsolvable problem. That was back in 2012; today no-one calls KRAS undruggable anymore. The first thing we did - and continue to do - was to take a systematic, blanket approach to KRAS. This level of commitment sets us apart from others. Our intention was never to have just one or two KRAS projects. Instead, we set the strategic goal to establish a cluster of KRAS projects.

    The cluster has been building year on year, with existing projects sparking new ones and chemistry breakthroughs opening up opportunities in biology and vice versa. Our guiding principle as we set out was, “Let’s inhibit KRAS as directly and specifically as possible.” This sounds easy but there’s a catch. KRAS belongs to a class of drug targets where, instead of turning an enzyme or protein off as in the ‘key in the lock’ model, we have to stop two proteins coming together by finding protein-protein interaction (PPI) inhibitors, more like a screwdriver prising a door away from the frame. This class of proteins lacks the deep pockets that we chemists need to make drugs, so we needed to apply non-traditional approaches to be successful.

    A technology called fragment-based drug discovery, which involves probing disease-causing proteins with fragments of molecular ‘keys’ rather than complete ‘keys’, is the way to go to drug RAS and other such targets. But working with fragments requires a different mindset and skillset; you can’t do fragment-based drug discovery half-heartedly. That’s why we collaborated early in our endeavour with Professor Stephen Fesik, the pioneer of fragment-based drug discovery, at Vanderbilt University. For almost a decade now every chemist in our oncology team has dedicated themselves to fragment-based approaches.

    And that was the trick. Suddenly, working with fragments we discovered that KRAS and every other PPI target that we looked at, did, indeed, have pockets, all be it well hidden, shallow pockets. This was the ‘foot in the door’ and gave us a starting point with KRAS. And a second technology, alongside fragments, was instrumental in building our capabilities to successfully drug KRAS: protein crystallography, which uses X-rays to give three-dimensional images of how drug candidates fit into their ‘locks’. We’ve optimised our KRAS crystal systems to such an extent that we can now get a ‘3D-KRAS photo’ of almost every compound we make. These 3D-photographs enable our chemists to know exactly where every atom needs to be placed to make a KRAS drug. This is important because the KRAS fragments we start out with need to be improved a million-fold before they become potent drug molecules.

    Stopping feedback with SOS1 inhibition

    Cell signalling networks in cancer are extremely resilient. When we treat cancer cells with KRAS inhibitors, the KRAS signalling is shut down at the drug target and the ‘volume’ of signalling across the whole pathway is turned down. But, after a matter of only a few hours hours, the ‘volume’ goes up somewhere else in the network and signalling is restored. Termed feedback, this also needs to be addressed if we are to treat KRAS cancers effectively. So, we’re increasingly adding to our armament, of molecules, ones that block feedback in KRAS-driven cancer cells. And we’ve found an ideal target in SOS1, a protein named Son of Sevenless 1, which is responsible not only for turning KRAS on but is also the key feedback node in KRAS signalling.  If KRAS is the ‘beating heart’ of cancer, then SOS is its’ pacemaker. KRAS can’t ‘beat’ without SOS.

    SOS the pacemaker

    By selectively inhibiting SOS1, one of the two types of SOS, we are simultaneously slowing KRAS beating and blocking feedback. With feedback blocked, we are now able to permanently shut down KRAS signalling by combining SOS1 inhibitors with inhibitors of other key proteins in the RAS signalling pathway, such as MEK.

    Selective inhibition of SOS1, alone or in combination with MEK inhibition, is a therapeutic concept with the potential to treat all KRAS cancers irrespective of the KRAS-mutation type: a pan-KRAS inhibitor. And we’ve found that’s exactly what our SOS1 inhibitors can do. In contrast to KRASG12C inhibitors, our SOS1 inhibitors block the interaction of SOS1 with the inactive form of KRAS in a manner that is independent of KRAS mutation status. They are orally bioavailable and well-tolerated, and treatment leads to KRAS pathway inhibition which translates into tumor stasis in the laboratory. Even more exciting is that we see significant tumor shrinkage when our SOS1 inhibitor is combined with a MEK inhibitor.

    Looking to the future

    It’s a very, very exciting phase in KRAS research. We’ve now got a large portfolio of KRAS programmes with almost everyone in the Vienna team working or having worked on KRAS in one way or another, not to mention our many collaborators around the world. Digging deeper into understanding KRAS by leveraging our growing expertise with cutting-edge chemical and biological technologies means that new opportunities keep presenting themselves.

    The task that we are committed to is enormous: directly targeting KRAS, blocking feedback and ultimately getting ahead of resistance. It might take a generation to complete the task but 2019 marks an important milestone as the year that the first patients received experimental KRASG12C and pan-KRAS inhibitors, almost 40 years after the discovery of KRAS.  Boehringer Ingelheim is a family-owned company that thinks in generations. We have the long-term vision and scientific persistence to complete this task and put an end to KRAS cancers.

  • Drugging Cancer’s Big Four - Darryl McConnell

    Drugging Cancer’s Big Four

    In the early 1980s, when I just started taking my first chemistry classes in high school, we knew what the four biggest causes of cancer were – RAS, P53, MYC and beta-Catenin. These proteins are found in the human body, and when mutated, cause more than half of all cancers. Medicines that target these four proteins have the potential to transform life expectancy for most patients with cancer. These proteins play such critical roles in the life of the cancer cell and have proven so elusive in drug discovery that scientists have given them descriptive names such as, the “beating heart of cancer” (RAS), the “guardian of the genome” (P53) and the “master regulator” (MYC). Beta-Catenin is of such central biological importance that it even has its own “destruction complex” to ensure that it stays under control. Sadly, after more than 30 years of research, there are no drugs approved today against any of the “big four”. Drugging the “big four” is such a challenging and compelling aspiration that no chemist wanting to bring more innovation to chemistry should shy away from.

    Darryl McConnell

    Cancer is a disease of our genes with more than 100 different types of known cancers. In most cases, mutations in our genes accumulate over a period of 30 years and allow cancer cells to divide faster, become immortal and evade our immune system. The genome of cancer cells, unlike healthy cells, is inherently unstable. It contains up to a mind-boggling one trillion mutations, but only a few of these mutations actually drive the cancer. The remaining mutations are merely passengers. Mutations in RAS, P53, MYC and beta-Catenin are known to be the main drivers of cancer. RAS- driven cancers, for example, make up around 20% of all cancers, including almost all pancreatic cancers as well as more than 30% of lung cancers and almost half of all colon cancers.

    Classical drugs work like “keys” that fit into “locks” on the surface of disease-causing proteins and turn them off. No classical drugs have been found for the “big four” because they do not have “locks” on their surfaces. RAS, P53, MYC and beta-Catenin function through interacting with other proteins via large, flat, complementary surfaces and thus require a new class of drugs that scientists are calling Protein-Protein Interaction Inhibitors. The conundrum of how to make a “key” when there is no “lock” has led to the belief that RAS, P53, MYC and beta-Catenin are “undruggable”. However, modern chemical approaches are challenging this dogma. After much insight and determination, these high hanging fruits of cancer research are now within reach.

    At Boehringer Ingelheim, we have been able to discover “locks” on all the proteins we have explored so far using small pieces of drug molecules called “fragments”. Fragments provide a foothold for discovering drugs against proteins like the “big four,” but are just the very beginning in the drug discovery process. Developing these fragments into drugs has been made possible through developments at the juncture of biology, chemistry and physics. Using highly sensitive biophysical measurements, we are now able to detect almost any molecule that comes into contact with the surface of a protein. In addition, chemists are now able to generate three-dimensional photographs of protein-drug complexes (“lock and key”), where each individual atom is clearly visible. These photographs, called X-ray crystal structures, transform our chemists into atomic locksmiths able to precisely design the drug molecules of the future. I’m often asked, “What do we do if we fail to obtain X-ray crystal structures?” My answer is always, “We keep trying”. So far, we have always found a way. In fact, we have over 400 such photographs of KRAS itself - a KRAS movie if you will. This truly transforms our ability to design drugs.

    Modern drug discovery is not performed behind the closed doors of a pharmaceutical company, but in collaboration with the world’s academic leaders in the field. We are proud to have a growing network of collaborators who are also dedicated to making a big difference in the lives of patients, and who share our passion to drug the (so-called) undruggable. Our scientific interests and philosophies overlap so much with Professor Stephen Fesik and his team at Vanderbilt University, that we now have three key drivers of cancer on our list to develop drugs for – RAS, SOS and MCL1.  Together, with Alessio Cuilli and his team at the University of Dundee, we are investigating a completely new class of drugs called Proteolysis Targeting Chimeras (PROTACs), which represent one of the biggest innovations in chemistry in recent years.  Just a few kilometers from our research site, we are collaborating with Professor Robert Konrat and his group at the Max-Perutz Laboratories at the University of Vienna on arguably the most difficult class of proteins to drug - the so-called intrinsically disordered proteins such as MYC. 

    This is the first of a series of articles that will take a closer look at each of the “big four,” highlighting scientific breakthroughs and describing how Boehringer Ingelheim is drugging cancer’s big four in our pursuit of making cancers a chronic disease or dare it be said…curing cancers.

  • A transformative pathway in Immunology

    A transformative pathway in Immunology

    A transformative pathway in Immunology

    Dr. Jay Fine, Global Head of Immunology and Respiratory Diseases Research, talks about the innovative work on the IL36 pathway, which has significant potential to benefit people with a variety of chronic inflammatory and fibrotic diseases.

  • Translational Medicine in Immunology

    Translational Medicine in Immunology

    Translational Medicine in Immunology

    Learn how translational medicine can help to bring transformational therapies to patients.

  • Unlocking novel biology in immunology

    Unlocking novel biology in immunology

    Unlocking novel biology in immunology

    Dr. Jay Fine, Global Head of Immunology and Respiratory Diseases Research, talks about our ‘Blunt, Repair, Block’ approach to immunology research, and how this allows us to meet patients’ unmet medical needs.