What happens when we redraw the boundaries of drug discovery?

Expanding the map beyond conventional target inhibition

When I began my career as a physician-scientist, one of the most humbling realities I encountered was that having a strong biological insight did not always mean having a clear therapeutic path forward. Many diseases are driven by proteins we know are causally implicated — what we call strong causal human biology — but that does not mean scientists have learned how to modulate them. What some may see as an obstacle is something that we, as researchers, celebrate — the opportunity to discover new ways to turn these biological insights into patient benefit.

Conventional medicines rely on what we call occupancy-driven approaches. A small molecule might bind to a protein and block its activity, or an antibody might prevent a signaling event, leaving the protein itself in place. These approaches have been revolutionary. Yet, they are not always enough. Some disease drivers lack a clear “on-off switch” to inhibit. Others develop resistance over time, causing complex diseases like cancer to progress despite treatment.

Targeted protein degradation (TPD) offers a new way forward. Instead of merely inhibiting a protein’s activity, degraders take an event-driven approach, recruiting the cell’s natural disposal machinery to remove the disease-causing protein altogether. This modality does more than shut down function. It eliminates the culprit entirely.

The implications are profound. By harnessing the body’s natural degradation systems, degraders can bypass resistance mechanisms that blunt the effects of conventional inhibitors. They can reduce off-target toxicities by eliminating the source rather than competing for occupancy. And they can unlock therapeutic options for proteins once deemed “undruggable” because there was no obvious function to inhibit.

For patients, TPD offers a new opportunity when other approaches have failed. For scientists, it opens an entirely new way to think about matching modality to disease biology.

 How are CELMoD agents and LDDs expanding the frontier?

At Bristol Myers Squibb, our leadership in TPD includes expertise in CELMoD™ agents — highly selective molecular glues that enable precise targeting of disease-causing proteins. These small molecule degraders allow scientists to fine-tune degradation activity, extending our reach to a broad array of disease-relevant proteins.  

Our CELMoD agents reflect years of learning in molecular design, optimizing both potency and selectivity to degrade disease-causing proteins with precision. This approach has already changed how we think about drugging complex targets, and it continues to guide our discovery of next-generation degraders. Likewise, ligand-directed degraders (LDDs) are helping us expand into new biological territory, reaching targets once considered beyond the limits of conventional therapeutics. Together, these modalities form the backbone of our TPD platform —  one that’s already informing clinical development and laying the groundwork for what comes next.

What happens when scientists combine the best aspects of each modality?

These advancements become even more compelling when scientists combine the most promising modalities to create new opportunities. Among these is our work exploring degrader-antibody conjugates (DACs) — a next-generation approach that pairs the precise targeting abilities of antibodies with the event-driven removal of degraders.

By bringing together the guidance of an antibody and the cell’s natural degradation machinery, this approach has the potential to address disease drivers in tissues or cell types where precision targeting is key. This convergence expands our targeted protein degradation platform, making it more flexible, more sophisticated and, ultimately, more capable of addressing unmet needs.

This type of scientific convergence represents the next horizon for drug discovery and shows how far the foundational mechanism of targeted protein degradation can reach.

Turning bold science into firsts

Progress of this magnitude does not happen by chance. It is the result of years of sustained investment and a culture that embraces bold science.

At BMS, we are uniquely positioned to lead in this space. We are the only company with protein degraders already on the market, which gives us deep, practical experience in translating the promise of TPD into real patient benefit. Our CELMoD agent and LDD programs reflect that heritage and are paving the way for promising modalities like DACs that build on their success.

Behind the scenes, tools like AI and machine learning are accelerating this progress. We are using these technologies to expand our library of CELMoD agents, model protein-ligand interactions and screen cellular systems to identify degraders against disease-relevant targets. These capabilities allow us to generate stronger research hypotheses, iterate faster and focus development on the approaches most likely to succeed.

When I think about these advances, I see more than a pipeline. I see a powerful engine for innovation. Every step forward is the result of our teams working together across disciplines to solve hard problems.

Why this moment matters for drug discovery, and for patients

Protein degraders such as CELMoD agents, LDDs and emerging convergence modalities like DACs are not just new tools in the drug discovery toolbox — they represent a fundamental shift in how we approach disease. They are helping us redraw the map of what is “druggable,” expanding the range of biological mechanisms we can address and the number of patients we can help.

As a physician, I am reminded of the patients I treated who ran out of options. As a scientist, I see how far the field has come in just a few years, from theoretical promise to clinical reality. And as a leader, I am inspired by the teams here at BMS who are making it happen every day.

What excites me most is that we are still only at the beginning. By continuing to innovate in targeted protein degradation, invest in convergence approaches like degrader-antibody conjugates and apply emerging technologies such as AI, we are laying the groundwork for therapies that once seemed impossible.

This development exemplifies what it means to turn bold science into firsts, and why I believe the next chapter of drug discovery will be defined by how we continue to expand the map together.