Eric S. Fischer, PhD
Principal Investigator, Department of Cancer Biology, Dana-Farber
Professor of Biological Chemistry and Molecular Pharmacology, Harvard Medical School
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Degraders of PBRM1 as a Treatment of Melanoma and Renal Carcinoma
Project Overview
- The protein polybromo-1 (PBRM1) is linked to genome instability and aneuploidy. Inactivating mutations of these PBRM1 subunits have been found in 20% of human cancers, including renal cancer and melanoma.
- Dana-Farber researchers have developed small molecule degraders of PBRM1.
- Dana-Farber Cancer Institute is looking for the right partner with an interest in licensing this asset for further development.
Technology
Chromatin is a complex structure made up of DNA wound around histone proteins thereby condensing DNA to fit into the cell’s nucleus. Post-translational modifications of histones control DNA replication/transcription and down-stream protein expression.
Bromodomains are found in many chromatin-associated proteins including histones and reside within key chromatin modifying complexes controlling distinctive disease-associated transcriptional pathways e.g. the Switch/Sucrose Non-fermentable (SWI/SNF) chromatin-remodeling complex. The SWI/SNF is involved in gene regulation, cell lineage, and development, and is comprised of distinct bromodomain subunits including protein polybromo-1 (PBRM1) linked to genome instability and aneuploidy. Inactivating mutations of these PBRM1 subunits have been found in 20% of human cancers.
Hence, in addition to being a potential target for its role in immune response and inflammation, PBRM1 is a target of interest for the treatment of multiple malignancies including renal cancer and melanoma.
To exploit PBRM1 as a therapeutic target, the laboratory led by Dr. Eric Fischer at Dana-Farber has developed small molecule degraders of PBRM1 comprised of a ligand, capable of binding to the bromodomain of PBRM1, and a degron to recruit either Cereblon (CRBN) or Von Hippel-Lindau (VHL) ligases. Bringing PBRM1 near such a ligase enables its ubiquitination. Once ubiquitinated, PBRM1 is marked for degradation by the proteasome. As expected, Kelly cells treated for 6 and 24 hours with such a degrader showed near complete degradation of endogenous PBRM1 at a 10 μM degrader concentration, with visible decrease of protein abundance at 1 μM degrader concentration after 24 hours illustrating the therapeutic potential of selective PBRM1 degradation.
Novel PBRM1 degraders demonstrated:
- Cell-penetrating properties.
- Selective targeting of PBRM1.
- Potent degradation of PBRM1 in Kelly cells: 6h at 10μM and 24h at 1μM.
Team Members: Eric S. Fischer, PhD, Nathanael S. Gray, PhD, Radoslaw Nowak, DPhil, Katherine Donovan, PhD, Tinghu Zhang, PhD
Applications
Novel PBRM1 offering treatment opportunities:
- As a monotherapy or in combination with other therapies.
- In oncology, immune response, and inflammation.
- As pharmacologic agent to augment anti-tumor immune response for the treatment of malignancies including melanoma and renal cancer.
Opportunities
Dana-Farber Cancer Institute is looking for the right partner with an interest in licensing this asset for further development.
Team Members
Nathanael S. Gray, PhD
Professor of Chemical and Systems Biology, Co-Director of Cancer Drug Discovery, Stanford Medicine
Former Principal Investigator, Dana-Farber
Radoslaw Nowak, DPhil
Former Senior Scientist, Eric Fischer Lab, Dana-Farber
Katherine Donovan, PhD
Lead Scientist and Managing Director, Fischer Labs, Dana-Farber
Tinghu Zhang, PhD
Former Senior Scientist and Chemistry Group Leader at the Center of Protein Degradation (CPD), Dana-Farber
