2. Academic Validation
  3. Discovery of XYD270 as a Potent, Selective, and Orally Efficacious BRD9 PROTAC for Cancer Therapy

Discovery of XYD270 as a Potent, Selective, and Orally Efficacious BRD9 PROTAC for Cancer Therapy

  • J Med Chem. 2026 Mar 26;69(6):6634-6655. doi: 10.1021/acs.jmedchem.5c02858.
Yumin Huang 1 2,  Guizhen Cheng 1 3,  Xin Tang 1 4,  Zhiming Chen 1 2,  Cheng Zhang 1 2,  Jiankang Hu 1,  Xiaoshan Chen 1 2,  Jun Wang 5,  Zhaoming Chen 6,  Mohan Zhao 7,  Jinsong Liu 7,  Tingting Xu 1,  Jinming Ma 3,  Yan Zhang 1,  Bin Lin 5,  Hui Shen 1,  Yong Xu 1 4 5
Affiliations

Affiliations

  • 1 China-New Zealand Joint Laboratory on Biomedicine and Health, Guangdong Provincial Key Laboratory of Biocomputing, Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
  • 2 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 Institute of Health Sciences and Technology, Institutes of Physical Science and Information Technology, Anhui University, Hefei 230601, China.
  • 4 GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou 511436, China.
  • 5 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 6 Guangdong Provincial Key Laboratory of Biocomputing, Center for Biomedical Digital Science, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
  • 7 Pamplona Therapeutics, Shenzhen 518107, China.
PMID: 41782172 DOI: 10.1021/acs.jmedchem.5c02858
Abstract

BRD9, a unique component of the ncBAF complex, has emerged as a promising therapeutic target in various cancers such as synovial sarcoma (SS) and acute myeloid leukemia (AML). Herein, we report the design, synthesis, and biological evaluation of BRD9 PROTACs based on diverse cereblon-binding ligands. Through structure-activity study, we identified 32 (XYD270) as a highly potent PROTAC demonstrating excellent degradation activity in HS-SY-II cells (DC50 = 0.082 nM, Dmax = 96%) and MV4;11 cells (DC50 = 3.9 nM, Dmax = 90%). Notably, 32 displayed robust antiproliferative activity in MV4;11 cells (IC50 = 50 nM) and HS-SY-II cells (IC50 = 1.65 μM). In an MV4;11 xenograft model, once-daily administration of 32 (10 mg/kg) achieved significant tumor growth inhibition (TGI = 54%). Taken together, our findings establish 32 as a promising BRD9 PROTAC with compelling preclinical efficacy in SS and AML.

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