Protein Homeostasis 101: A Q&A with Josh Hansen 

May 26, 2020

Y

ears before Josh Hansen , director of chemistry at Bristol Myers Squibb’s San Diego R&D site,  found his calling in biopharma researching protein degradation, he had his sights set on a career in education. With that in mind, see below for a crash course on the important science being done in Josh’s lab, and how it may have an impact on patients who need it most.

Q: What is protein homeostasis?

A: Protein homeostasis is a field of study dedicated to maintaining the equilibrium of proteins in the human body.  

Proteins are important, complex molecules, each with a specific function within your body – some are vital to tissue structure, others are concerned with organ function, and so on. Because they’re so important, the body has an intricate system that is constantly making and remaking proteins (creation), while also removing ones that have become inactive or mutated (degradation). When a cell is unable to degrade certain proteins, the proteins can accumulate, causing diseases like cancer.

That’s where we come in — the goal of our work in protein degradation is to harness the body’s natural ability to target and remove specific proteins that are causing issues, to maintain homeostasis and keep patients healthy. 

Q: How does protein degradation differ from other therapeutic approaches?

A: Protein degradation allows us to target certain disease-causing proteins that were previously considered “undruggable,” and may also help overcome challenges associated with mutation.

Traditionally, many approaches to treating disease are focused on pathway inhibition – preventing specific proteins from being expressed or synthesized. Many of these approaches work incredibly well, but then become stymied when the targeted protein or cell mutates, rendering inhibition less effective. In addition, only about 10 percent of all human proteins can be targeted this way, translating into a huge opportunity for protein degradation to have an impact for patients who may not respond to available therapies. 

Q: What are CELMoD® compounds?

A: Cereblon E3 ligase modulators (CELMoD® compounds) promote protein degradation to remove disease-causing proteins from cells, eliminating their functioning altogether.

CELMoD compounds are small molecular weight compounds that work with an E-3 ligase called cereblon, an enzyme in the protein homeostasis cascade. CELMoD compounds act as a sort of “molecular glue” – co-opting the function of the protein cereblon to recruit targeted proteins that would otherwise not be degraded, and tagging them for the body’s natural removal system. These target proteins often play a role in disease pathophysiology, and early data show their elimination may have therapeutic benefit for some diseases.

Q: How is the field evolving over time? 

A: Today’s pipeline is directly built on our deep understanding of earlier discoveries in the protein degradation space. 

As a company we have several CELMoD compounds being evaluated across a handful of disease areas, as well as two approved immunomodulatory imide drugs (IMiD® agents), a subset of CELMoD compounds. 

IMiD agents modulate the immune system and other biological targets through multiple mechanisms of action, and have made a significant impact on the treatment landscape, and for patients. Based on our extensive experience with IMiD agents, we designed the “next generation” of CELMoD compounds to be much more targeted and have the potential to specifically help patients overcome resistance or treatment sensitivity. While IMiD agents were developed using empirical data, time and research have given us the opportunity to understand the mechanisms of action on a deeper level, and this has been an invaluable resource as we develop new therapies. 

Today, we have the potential to target thousands of proteins that we couldn’t have imagined were possible to reach even five years ago. From here, we are working to identify which have therapeutic utility – figuring out the right proteins to target, when and where. 

Q: From a personal perspective, what impact do you hope your research may have on patients?

A: It’s clear we are just scratching the surface in terms of potential impact here. I want to focus on creating new therapies that go beyond what’s currently available, to provide patients with as much time and hope for the future as possible.

With blood cancers specifically, there are so many patients who relapse and have a very short window of time left. If you look at a disease like acute myeloid leukemia (AML) – there is so little that we can do for these patients right now therapeutically, and that’s extremely distressing. 

The potential here goes beyond blood cancer, too – hematology is the first area where we saw the benefit for these therapies, but we are beginning to see utility in other diseases as well, including patients with solid tumors and immune-mediated diseases like lupus.  

It’s such an incredible time to be in drug discovery, and the thought of what this research could do for patients around the world is truly inspiring. I’m honored to be a part of it. 

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