As senior vice president of Discovery Biotherapeutics at Bristol Myers Squibb, Ho Sung Cho leads a team of talented researchers advancing novel protein and antibody-based therapies with the potential to treat disease. Cho is based in Bristol Myers Squibb’s San Diego research & early development site – a vibrant innovation hub for life sciences – where his team is focused on the exploration of novel biology and target concepts such as protein degradation and complex biologics.
In a recent MedCity Pivot Podcast, Cho shared insights into his approach to drug discovery and how Bristol Myers Squibb is building on decades of experience in the protein degradation space to bring novel assets into the clinic.
Bristol Myers Squibb’s – then Celgene’s – investigation of protein homeostasis began more than two decades ago with the launch of its first protein degrader. Building on this deep understanding of earlier discoveries in the protein degradation space, the company has brought six additional protein degraders into the clinic, giving them extensive development experience in this area.
Protein homeostasis is a field of study dedicated to maintaining the equilibrium of proteins in the human body. Cells have a built-in system for disposing of and recycling proteins and maintaining protein homeostasis. When a cell is unable to dispose of certain proteins, they can accumulate, causing cancer and other diseases. Protein degradation is the process by which proteins are destroyed in a cell. With targeted protein degradation, researchers are harnessing the cell’s own machinery to degrade several proteins that were previously considered “undruggable.”
“Normally when we think about drugging a target, we think about either antagonizing or agonizing the target,” said Cho. “What we do with the protein homeostasis drug is we target the protein or target of interest to be degraded by the proteasome so that you basically remove it from the cellular biology, as opposed to just blocking the enzymatic function of a protein. This allows us to go after targets that would be normally viewed as undruggable or difficult to drug.”
Cho observed that protein degraders have made a significant impact on the treatment of hematologic cancers and patients who, until recently, had few treatment options.
“We have seen a real shift in terms of multiple myeloma treatment, and what that means in terms of survival,” said Cho. “With newer medicines we’ve been able to shift the cancer closer to a chronic condition that is more manageable.”
Based on learnings from the company’s early research in targeted protein degradation, Bristol Myers Squibb is now focused on studying several novel Cereblon E3 Ligase Modulation Drugs that could potentially address a broader range of diseases, alone or in combination with other agents. These compounds act as a “molecular glue” to alter the protein-binding properties of cereblon to promote interaction with disease-causing proteins that would not typically be degraded.
“These agents are being investigated in different types of blood cancers such as multiple myeloma and acute myeloid leukemia, as well as solid tumors and immune-mediated diseases like lupus,” said Cho. “In fact, a study on one of our novel protein degraders was recently published on the cover of Blood, which is something we’re very proud of,” said Cho. “BMS is also evaluating ligand-directed degraders. This approach is being studied with an androgen receptor degrader currently in a Phase 1 study for castration resistant prostate cancer.”
With the steady progress being made in the protein degradation field, Bristol Myers Squibb is working to identify which proteins have therapeutic utility to give patients as much time and hope as possible.
To access the full podcast interview with Cho, where he discusses his approach to drug discovery, perspectives on dealing with failure, and some of the work his teams are doing in the protein degradation and COVID-19 spaces, click here.
Photo: appledesign, Getty Images
