Science Firsthand is a storytelling platform from Bristol Myers Squibb that celebrates the countless moments along the path from drug discovery through development – unique moments that have the potential to lead to major scientific breakthroughs that ultimately transform the lives of patients. This episode focuses on the company’s storied history in protein degradation, shining a light on the moment that our team opened the doors of possibility to intentionally designed protein degraders.
[00:00-00:09] M. Pourdehnad
The moment that you realize something that you've worked on since it was in the lab and coming into the clinic helps a patient is like a dream come true.
[00:10-00:34] M. Pourdehnad
Drug development really requires scientific rigor, discipline. You have to have the expertise, you need to be creative, but there's serendipity and you need to be ready and to see it. And then that's where like really incredible breakthroughs happen.
[00:35-00:50] N. Bence
The story really began 2 decades ago when BMS was one of the first companies to begin the study of immunomodulatory drugs in blood cancers. They’ve become the standard of care and continue to have a profound impact for patients lives.
[00:51-01:01] N. Bence
At the time, we had very little insight into exactly how these molecules were working.
[01:02-01:18] M. Pourdehnad
Back in 2010, scientists in Japan discovered that immunomodulatory drugs or IMiD drugs bound a protein called cereblon, and cereblon is part of the protein degradation system in cells.
[01:19-01:45] N. Bence
Now the story got really interesting because around 2014, a number of really important publications came out from Harvard scientists, internal research at BMS and also our Japanese colleagues, in which we began to understand that not only were these compounds binding to cereblon, but in fact they were actual molecular glues.
[01:46-01:57] N. Bence
It was a light bulb moment. The impact of understanding how the IMiD compound works...it gave rise to a whole new field of targeted protein degradation.
[01:58-02:16] N. Bence
And really there was an early understanding that targeted protein degradation, as represented by the IMiD compounds, might in fact represent essentially the tip of the iceberg for what that new modality could bring to patients.
[02:17-02:54] N. Bence
At the time, when you see like just an incredible, beautiful piece of scientific research, drug discovery and clinical development, it's something that is it's quite awe inspiring. As we begin to understand what are sort of the rules of the road for targeted protein degradation…it allows you to begin to think about the medical problem you want to solve, the disease causing protein that's affiliated with it and now perhaps intentionally design a molecule with the chemical structure required to create that completely novel molecular glue to recruit that disease-causing protein.
[02:55-03:11] M. Pourdehnad
Proteins are the functional molecules in a cell and the cell needs to regulate their production, modify them, and then get rid of them when they're not supposed to be around. And the getting rid of them is through protein degradation. It's the cells recycling system.
[03:12-03:15] M. Pourdehnad
We have several approaches to protein degradation at Bristol Myers Squibb.
[03:16-03:33] M. Pourdehnad
One of those, and the most advanced are the CELMoDTM agents. These drugs act as small molecular glues. They bring disease causing target proteins to cereblon and then target them for degradation. They are the furthest along in our pipeline and nearest term impact for patients.
[03:34-03:48] M. Pourdehnad
Another approach we have to protein degradation are ligand directed degraders. Ligand directed degraders are three-part molecules. They have a binder that binds cereblon, a linker and then a binding end moiety that binds the target protein.
[03:49-03:59] M. Pourdehnad
LDDs have opened up a new target space as well and it's exciting that we have one that's advanced in solid tumors and reached proof of concept.
[04:00-04:19] M. Pourdehnad
There's also some disease-causing targets where we can use these degrader antibody conjugates. The antibodies bring the degrader to the specific cell expressing a protein and only those cells you get the degradation. So it allows a selectivity that can really widen the therapeutic index of those drugs.
[04:20-04:28] M. Pourdehnad
Having these multiple approaches to protein degradation really allows us to match the right modality to the disease.
[04:29-04:38] M. Pourdehnad
As we advance these degraders, we're really leveraging our expertise at Bristol Myers Squibb and that includes using artificial intelligence and machine learning.
[04:39-05:04] M. Pourdehnad
A hundred percent of these small molecule degraders and LDDs are now being supported by what we call “Predict First”, where the chemists are being assisted by these machine learning algorithms to predict first which molecules to make and test and then to feed the algorithm to optimize our drugs to get them to patients faster.
[05:05-05:25] N. Bence
New modalities do not come along very often. And so when they do, there's great promise, and there's also a phase in which the field is going through this incredible sort of rapid and creative expansion. And it's one of the main motivations for our BMS scientists to drive forth novel medications for patients who need them most.
[05:26-05:47] M. Pourdehnad
I was inspired to become a physician scientist because I loved science, but also because I had a friend when I was a child who had leukemia. To see him go through that and really the medicines to fail and not help him inspired me to apply what I do to develop new medicines for patients who don't have available therapies.
[05:48-06:08] M. Pourdehnad
It's been such an incredibly fulfilling journey to see therapies that we've worked on from the earliest days to actually help patients. It just keeps you motivated to keep going, you know, keep working on the next innovation for the patients.
The discovery moment — a culmination of bold science, relentless pursuit and cross-functional collaboration — is quite hard to describe. Yet, it’s these moments where the potential of a compound is realized that continue to inspire our R&D teams. But these breakthroughs don’t happen by chance — they are driven by our science-powered approach guided by our R&D principles and patient-centric focus. In areas like targeted protein degradation, we’re not just advancing medicine — we’re redefining what’s possible for patients.
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Beyond just relevant information about Bristol Myers Squibb's therapeutic areas and innovation, Our stories offer a window into the work our employees do every day for patients.
Research and development teams at Bristol Myers Squibb take a unique approach to the path of drug development. Our scientists pursue diverse research approaches, where they glean insights on disease targets and their potential effect on human biology and efficiently implement those learnings into drug discovery research in the lab. Guided by our R&D principles, we focus on selecting the right targets based on human biology, matching the right kind of medicine to the biological mechanism of disease and generating early evidence that an idea is working to increase the probability of successfully delivering meaningful medicines to patients faster than ever. This approach has fueled breakthroughs across our research platforms, including our leadership in protein degradation, and decades of success at both the disease and molecular levels have provided us with unmatched clinical data to inform our scientific path forward.
Bristol Myers Squibb remains the only company that has successfully developed and commercialized protein degrader agents. BMS’ legacy in protein degradation — an approach through which researchers can harness the body’s natural ability to target and remove unnecessary or harmful disease-causing proteins to maintain a healthy equilibrium — began more than 20 years ago, with Celgene’s (now BMS’) development of the early IMiD® compounds to treat blood cancers. Today, it stands as a prime example of how the company’s scientific expertise and collaborative R&D environment channel curiosity into exploration to tackle some of science’s toughest questions.
The drug development path doesn’t stop once medicines make their way bedside — teams at Bristol Myers Squibb are focused on a continual information circuit back into the lab. Insights across the drug discovery and development continuum are shared with internal experts, who analyze these data and bring learnings back to the biologists and chemists in the lab to improve research methods and future hypotheses.
Researchers had been looking into IMiD® compounds for decades, but no one had any idea how and why they worked — the evidence was in the clinical outcomes. In the 2010s, scientists made several discoveries that offered stunning clarity and advanced the whole field forward. Namely, we began to understand that these compounds were molecular glues, or small molecules that promote protein-protein interactions. Molecular glues often bring a target protein and an E3 ubiquitin ligase together to trigger protein degradation. In doing so, disease-causing proteins previously considered “undruggable” can be targeted for therapeutic benefit. Today, targeted protein degraders are being designed with greater precision, agility and insight to address validated and novel disease targets in both oncology and hematology.
Researchers are now pursuing multiple paths to the discovery and development of protein degraders, providing more opportunities for breakthroughs and diverse therapeutic strategies. We are leveraging three different modalities of protein degradation: molecular glues (CELMoD™ agents), ligand-directed degraders (LDDs) and degrader antibody conjugates (DACs), with current programs addressing both hematologic malignancies and non-malignancies, as well as solid tumors. This three-pronged approach enables us to match the right therapeutic modality with the underlying biology, maximizing impact on disease targets and opening the door to more meaningful breakthroughs for patients.
Protein degraders are just one example of how relentless scientific curiosity can unlock new possibilities for patients. Our scientists work tirelessly every day to uncover insights that may lead to transformative treatments for patients in need, supported by innovation in the lab and state-of-the-art technological capabilities, including AI and machine learning. However, these tools don’t function in isolation. Our teams are uniquely trained at the intersection of computer science and biology, ensuring that every step supported by AI in our collaborative hybrid intelligence efforts is grounded in human biology and disease expertise. From analyzing data and identifying potential targets to completing components of clinical and regulatory documents, these technologies are helping to advance medicines to patients faster than ever before.
While these technologies have accelerated timelines and enhanced R&D efficiency, it's equally important to reflect on the rich legacy of scientific discovery and seek inspiration and deeper understanding from these breakthroughs as we work to shape the future of science and medicine.
Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. As global citizens, we work sustainably and responsibly to create a positive impact in the communities where we live and work.
