Antibody-Mediated Delivery of BRM/BRG1 Protein Degraders Affords Strong Antitumor Efficacy in Multiple BRM-Dependent Non-Small Cell Lung Cancer Xenograft Models
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.
Authors
- Yanmei Xin (ORCID: https://orcid.org/0000-0002-5216-6681)
- Shang‐Fan Yu (ORCID: https://orcid.org/0009-0002-2625-663X)
- Thomas Januario
- Martine Darwish (ORCID: https://orcid.org/0000-0003-4490-2164)
- Yusi Cui (ORCID: https://orcid.org/0000-0003-1198-5960)
- Isidro Hötzel (ORCID: https://orcid.org/0000-0001-6910-7840)
- X F Wang
- Rebecca K. Rowntree (ORCID: https://orcid.org/0009-0004-7382-6417)
- Ying Lü (ORCID: https://orcid.org/0000-0002-8828-169X)
- Summer A. Baker Dockrey
- Xiaofen Ye (ORCID: https://orcid.org/0009-0001-4465-1839)
- Donglu Zhang (ORCID: https://orcid.org/0000-0001-8677-9737)
- Peter S. Dragovich (ORCID: https://orcid.org/0000-0001-7372-2862)
- Shabkhaiz Masih (ORCID: https://orcid.org/0000-0003-2614-9375)
- Julien Lafrance‐Vanasse (ORCID: https://orcid.org/0000-0001-8807-6277)
- Robert L. Yauch (ORCID: https://orcid.org/0000-0001-9478-6283)
- Christopher M. Rose (ORCID: https://orcid.org/0000-0002-7502-3368)
- Ely Cosino (ORCID: https://orcid.org/0009-0007-3164-1045)
- Thomas H. Pillow (ORCID: https://orcid.org/0000-0001-7300-1002)
- Woody Perng
- Jack Sadowsky (ORCID: https://orcid.org/0000-0001-9872-1284)
- Pravin Chandra (ORCID: https://orcid.org/0000-0002-6555-3832)
- Yi-Xiang Wang (ORCID: https://orcid.org/0000-0002-5246-5497)
- Mary Ann Go
- Geoffrey Del Rosario
- Mingtao He
- Shu Chen
- Rachana Ohri
- Richard Vandlen
- Chunsing Li
- Joyce Liu
- Nikkia Hamidi
- John Wai
- Stephanie Dale
- Nicholas Dompe
- Stephanie Monson
- Douglas Leipold
- William Sawyer
- Huifen Chen (ORCID: https://orcid.org/0000-0001-8273-9295)
- Tommy K. Cheung
- Hartmut Koeppen
- Fang Zhang
- Nancy Zhang
Institutions
- WuXi AppTec (China) (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-05-17
- DOI
- https://doi.org/10.1021/acs.jmedchem.6c00592
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 0.00