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

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

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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