Antibody-Mediated Delivery of BRM/BRG1 Protein Degraders Affords Strong Antitumor Efficacy in Multiple BRM-Dependent Non-Small Cell Lung Cancer Xenograft Models

  • J Med Chem. 2026 May 28;69(10):12583-12618. doi: 10.1021/acs.jmedchem.6c00592.
Summer A Baker Dockrey  1 ,  Pravin Chandra  1 ,  Huifen Chen  1 ,  Shu Chen  1 ,  Tommy K Cheung  1 ,  Ely Cosino  1 ,  Yusi Cui  1 ,  Stephanie Dale  1 ,  Martine Darwish  1 ,  Nicholas Dompe  1 ,  Geoffrey Del Rosario  1 ,  Mary Ann Go  1 ,  Nikkia Hamidi  1 ,  Mingtao He  2 ,  Isidro Hötzel  1 ,  Thomas Januario  1 ,  Hartmut Koeppen  1 ,  Julien Lafrance-Vanasse  1 ,  Douglas Leipold  1 ,  Chunsing Li  3 ,  Joyce Liu  1 ,  Ying Lu  3 ,  Shabkhaiz Masih  1 ,  Stephanie Monson  1 ,  Rachana Ohri  1 ,  Woody Perng  1 ,  Thomas H Pillow  1 ,  Christopher M Rose  1 ,  Rebecca K Rowntree  1 ,  Jack Sadowsky  1 ,  William Sawyer  1 ,  Richard Vandlen  1 ,  John Wai  3 ,  Jian Wang  3 ,  XinXin Wang  3 ,  Yanmei Xin  2 ,  Xiaofen Ye  1 ,  Shang-Fan Yu  1 ,  Donglu Zhang  1 ,  Fang Zhang  2 ,  Nancy Zhang  1 ,  Robert L Yauch  1 ,  Peter S Dragovich  1
Affiliations
  • 1. Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 2. Pharmaron Beijing, Co. Ltd., 6 Tai He Road, BDA, Beijing 100176, P. R. China.
  • 3. Wuxi Apptec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
PMID: 42144767 DOI: 10.1021/acs.jmedchem.6c00592
Abstract

The synthesis and biological characterization of multiple degrader antibody conjugates (DACs) bearing a heterobifunctional VHL-dependent proteolysis targeting chimera (PROTAC) payload is described. The conjugated molecule (A515) potently and extensively degrades the BRM protein (also known as SMARCA2) in cell-based assessments and exhibits moderate degradation selectivity for BRM over the closely related paralog protein BRG1 (SMARCA4). A CD71-targeting DAC that utilizes A515 as a payload and employs a disulfide-based linker affords strong, antigen-dependent efficacy in an H1944 xenograft model. Similarly, a Trop2-targeting DAC-bearing A515 that incorporates a protease-cleavable linker provides potent BRM degradation outcomes in HCC515 in vitro assessments along with encouraging antigen-dependent antitumor activity in several HCC515-based xenograft experiments. Structure-activity relationship information based on in vitro BRM degradation results and single-dose in vivo pharmacodynamic experiments is also provided for several additional CD71 and Trop2-targeting DACs in which the nature of the linkers and the A515 attachment sites are varied.

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