Novel Bruton’s Tyrosine Kinase (BTK) Degraders

Project Overview

• Bruton’s tyrosine kinase (BTK) facilitates B cell receptor signalling cascades in many B cell malignancies, such as mantel cell lymphoma (MCL), chronic lymphocytic leukemia, or Waldenström macroglobulinemia.
• Several BTK inhibitors (e.g., ibrutinib) have been clinically approved, however many patients do not respond to therapy or eventually acquire resistance. Developing treatment strategies to prevent or overcome BTK inhibitor resistance remains an urgent, unmet need. 
• Dana-Farber scientists have developed a portfolio of potent and highly selective PROTAC degraders targeting BTK.
• The portfolio of BTK degraders is available for licensing.

Technology

Dana-Farber scientists have developed a portfolio of potent and highly selective PROTAC (proteolysis-targeting chimeras) degraders targeting BTK. PROTAC degraders are small molecules that remove or otherwise break down disease-causing proteins.

These degraders induce complete destruction of the BTK protein, thereby reducing the likelihood of resistance mechanisms. In addition, the researchers discovered that these compounds also induce degradation of IKZF1 and IKZF3, which are essential transcription factors for B cell malignancies, resulting in compositions that attack cancer via a “triple degradation” strategy. 

An optimized lead compound was identified, and in vitro and in vivo xenograft studies were performed which demonstrated sustained depletion of the BTK protein, antiproliferation of cancer cells, reduced tumor burden, and increased survival. The exciting therapeutic promise of this technology was highlighted in a special commentary article in Blood. (See: Chiron, David. “Three targets in 1 shot against ibrutinib resistance.” Blood, The Journal of the American Society of Hematology 133.9 (2019): 888-889.

Further Details:

Huang, Hai-Tsang, et al. “A chemoproteomic approach to query the degradable kinome using a multikinase degrader.” Cell chemical biology 25.1 (2018): 88-99.

Dobrovolsky, Dennis, et al. “Bruton tyrosine kinase degradation as a therapeutic strategy for cancer.a“ Blood, The Journal of the American Society of Hematology 133.9 (2019): 952-961.

Team Members: Nathanael S. Gray, PhD, Dennis Dobrovolsky, PhD, Hai-Tsang Huang, PhD, Li Tan, PhD

Applications

• Treatment of BTK-dependent cancers, especially B-cell malignancies 
• Treatment of ibrutinib-resistant forms of B-cell malignancies 

Opportunities

Dana-Farber Cancer Institute is looking for the right partner with an interest in licensing this asset for further development