The Path to a Protein Degrader
Protein Degradation at Bristol Myers Squibb
Bristol Myers Squibb’s investigation of protein degradation began more than two decades ago. Building on this legacy and scientific expertise, Bristol Myers Squibb is discovering and developing therapeutic approaches in blood cancers, solid tumors and other therapeutic areas with high unmet need.
Protein degradation is the process by which proteins are naturally destroyed in a cell. With targeted protein degradation, researchers are harnessing the cell’s own machinery, for example ubiquitin ligase (E3) enzymes, to degrade several classes of proteins that were previously considered “undruggable.”
Learn more about the basics of protein degradation here.
The science behind the discovery and development of protein degraders has evolved over time.
Early protein degraders were discovered and developed based on the observed effect they had on the individual and without a clear picture of how they worked in the body.
Newer protein degraders are being developed from the beginning to have a specific therapeutic effect achieved by a specific mechanism of action.
Cryogenic electron microscopy allows researchers to see the details of protein structures and how proteins interact with one another. This has enabled purposeful advancements and driven the field of protein degradation forward.
Bristol Myers Squibb recognized the importance of this imaging technology early and invested in equipping labs and researchers with it in order to advance the company’s rational design capabilities.
Discovery and Development
Researchers at Bristol Myers Squibb are leveraging two different methods of protein degradation: molecular glues (CELMoDTM agents) and heterobifunctional agents (also called ligand-directed degraders, or LDDs).
Pursuing multiple paths to the discovery and development of protein degraders provides more opportunities for breakthroughs and therapeutic strategies that could one day help patients.
Although both paths may lead to a protein degrader agent, the development process looks very different, each with its own sophisticated technology and research experts.
It all begins with the CELMoDTM library
- Bristol Myers Squibb has built an industry-leading CELMoDTM library using computational and medicinal chemistry
- CELMoDTM from the library are screened through relevant cells
- The disappearance of proteins is measured
Choosing a potential target
- Researchers examine the proteins that disappeared to determine their relevance in various diseases
- This identifies which CELMoDTM/target pairs researchers will take forward to the optimization step
LDDs are 3-component molecules (two different protein binders joined by a linker) designed to bring together target proteins with key components of the protein degradation cellular machinery, redirecting the machinery to degrade the target proteins.
It all begins with a target
- Researchers identify target proteins implicated in a disease with the aim of removing them from the cells
Building an LDD
- Scientists begin building the LDD starting with the end that interacts with the identified target of interest
- This molecule is often found through our internal screening platforms
- The linker, or middle component, is then attached
- Finally, a molecule on the opposite end that binds the protein degradation cellular machinery is connected to the linker
Potential protein degraders from both approaches are tested and optimized through various preclinical studies and processes.