ePoster Display session ePoster

43P - Pre-clinical evaluation of potent and orally bioavailable next-generation inhibitors targeting the family of mutants that drive oncogenic BRAF dimer formation (ID 268)

Presentation Number
43P
Lecture Time
10:01 - 10:01
Speakers
  • Yoon-Chi Han (New York, YT, United States of America)
Session Name
ePoster Display session
Room
ePoster gallery
Date
Tue, 02.03.2021
Time
08:00 - 20:00
Authors
  • Yoon-Chi Han (New York, YT, United States of America)
  • Pui Yee Ng (Cambridge, AL, United States of America)
  • Ryan Schulz (New York, NY, United States of America)
  • Shao Ning Yang (New York, United States of America)
  • Alana Lelo (New York, United States of America)
  • Luisa Shin Ogawa (Cambridge, United States of America)
  • Matthew O'Connor (New York, NY, United States of America)
  • Noboru Ishiyama (Cambridge, United States of America)
  • Ivan Jewett (Cambridge, MA, United States of America)
  • Darlene Romashko (New York, NY, United States of America)
  • Andrei Salomatov (Cambridge, MA, United States of America)
  • Shalabh Thakur (Cambridge, MA, United States of America)
  • Sherri Smith (Cambridge, MA, United States of America)
  • Elizabeth Buck (New York, NY, United States of America)
  • Christopher Roberts (Cambridge, MA, United States of America)
  • Matthew Lucas (Cambridge, MA, United States of America)
  • Tai-An Lin (New York, United States of America)

Abstract

Background

The canonical BRAF V600E (class I) mutation is a potent oncogene which is uniquely active as a RAS-independent monomer, and which has been successfully targeted by several FDA-approved inhibitors. While active against monomeric BRAF V600E, these first generation BRAF inhibitors induce paradoxical activation of RAS-driven BRAF dimers in cells expressing wild-type RAF, and this can lead to secondary malignancies. More recently, numerous non-canonical BRAF oncogenic mutations including BRAF-fusions have been described as oncogenes that drive RAS-independent (class II) or RAS-dependent (class III) dimers. These non-canonical dimeric BRAF oncogenes are resistant to the first-generation drugs, effective only against the monomeric BRAF V600E mutation. Discovery of an inhibitor directed against the family of dimeric BRAF oncogenic mutations which avoids paradoxical activation is a major unmet need.

Methods

We applied our proprietary Mutation-Allostery-Pharmacology (MAP) platform technology developed by Black Diamond Therapeutics to identify and validate a group of previously uncharacterized non-canonical oncogenic class II and class III BRAF mutation clusters. We further demonstrate that this ensemble of both novel and previously validated non-canonical oncogenic BRAF mutants can form the basis of a differentiated drug discovery program aimed at identifying small molecules that potently and selectively target this family of dimeric BRAF mutations.

Results

Herein, we describe a series of small molecule inhibitors with potent anti-proliferative activity directed against tumor cells harboring dimer-inducing BRAF oncogenic mutations and which are devoid of paradoxical RAF activation. Leading exemplars of BDTX compounds are orally available inhibitors that achieve target engagement of BRAF dimer oncogenes in vivo and robust anti-tumor efficacy in xenograft models in mice.

Conclusions

These data support continued development of rationally designed molecules targeting a broad range of non-canonical BRAF dimer-promoting mutations to extend the prospect of precision medicine in patients with BRAF mutant tumors.

Legal entity responsible for the study

Black Diamond Therapeutics.

Funding

Black Diamond Therapeutics.

Disclosure

Y-C. Han, P.Y. Ng, R. Schulz, S.N. Yang, A. Lelo, L.S. Ogawa, M. O'Connor, N. Ishiyama, I. Jewett, D. Romashko, A. Salomatov, S. Thakur, S. Smith, E. Buck, C. Roberts, M. Lucas, T-A. Lin: Shareholder/Stockholder/Stock options, Full/Part-time employment: Black Diamond Therapeutics.

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