PROTACs Targeting BRM (SMARCA2) Afford Selective In Vivo Degradation over BRG1 (SMARCA4) and Are Active in BRG1 Mutant Xenograft Tumor Models

  • J Med Chem. 2024 Jan 5. doi: 10.1021/acs.jmedchem.3c01781.
Michael Berlin  1 ,  Jennifer Cantley  1 ,  Mark Bookbinder  1 ,  Elizabeth Bortolon  1 ,  Fabio Broccatelli  2 ,  Greg Cadelina  1 ,  Emily W Chan  2 ,  Huifen Chen  2 ,  Xin Chen  1 ,  Yunxing Cheng  3 ,  Tommy K Cheung  2 ,  Kim Davenport  1 ,  Dean DiNicola  1 ,  Debbie Gordon  1 ,  Brian D Hamman  1 ,  Alicia Harbin  1 ,  Roy Haskell  1 ,  Mingtao He  3 ,  Alison J Hole  4 ,  Thomas Januario  2 ,  Philip S Kerry  4 ,  Stefan G Koenig  2 ,  Limei Li  3 ,  Mark Merchant  2 ,  Inmaculada Pérez-Dorado  4 ,  Jennifer Pizzano  1 ,  Connor Quinn  1 ,  Christopher M Rose  2 ,  Emma Rousseau  1 ,  Leofal Soto  1 ,  Leanna R Staben  2 ,  Hongming Sun  3 ,  Qingping Tian  2 ,  Jing Wang  1 ,  Weifeng Wang  3 ,  Crystal S Ye  2 ,  Xiaofen Ye  2 ,  Penghong Zhang  3 ,  Yuhui Zhou  2 ,  Robert Yauch  2 ,  Peter S Dragovich  2
Affiliations
  • 1. Arvinas LLC, 5 Science Park, New Haven, Connecticut 06511, United States.
  • 2. Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 3. Pharmaron Beijing, Co. Ltd., 6 Tai He Road, BDA, Beijing 100176, P. R. China.
  • 4. Evotec (U.K.) Ltd., 95 Park Drive, Milton Park, Abingdon, Oxfordshire OX14 4RY, U.K.
PMID: 38180485 DOI: 10.1021/acs.jmedchem.3c01781
Abstract

The identification of VHL-binding proteolysis targeting chimeras (PROTACs) that potently degrade the BRM protein (also known as SMARCA2) in SW1573 cell-based experiments is described. These molecules exhibit between 10- and 100-fold degradation selectivity for BRM over the closely related paralog protein BRG1 (SMARCA4). They also selectively impair the proliferation of the H1944 "BRG1-mutant" NSCLC cell line, which lacks functional BRG1 protein and is thus highly dependent on BRM for growth, relative to the wild-type Calu6 line. In vivo experiments performed with a subset of compounds identified PROTACs that potently and selectively degraded BRM in the Calu6 and/or the HCC2302 BRG1 mutant NSCLC xenograft models and also afforded antitumor efficacy in the latter system. Subsequent PK/PD analysis established a need to achieve strong BRM degradation (>95%) in order to trigger meaningful antitumor activity in vivo. Intratumor quantitation of mRNA associated with two genes whose transcription was controlled by BRM (PLAU and KRT80) also supported this conclusion.

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