2. Academic Validation
  3. Discovery of a Highly Potent and Efficient BRD9 Degrader with Strong In Vivo Antitumor Activity

Discovery of a Highly Potent and Efficient BRD9 Degrader with Strong In Vivo Antitumor Activity

  • J Med Chem. 2026 Jun 11;69(11):13528-13550. doi: 10.1021/acs.jmedchem.6c00491.
Xin Tang 1 2,  Yumin Huang 2 3,  Cheng Zhang 2 3,  Yi Sun 2 3,  Qingqing Hu 2,  Guizhen Cheng 2 4,  Jiankang Hu 2,  Zhiming Chen 2 3,  Xiaohan Zhang 5,  Xiaoxi Zhuang 2,  Adam V Patterson 6,  Jeff B Smaill 6,  Xishan Wu 2,  Yan Zhang 2,  Yong Xu 1 2,  Hui Shen 2
Affiliations

Affiliations

  • 1 GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou 511436, China.
  • 2 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.
  • 3 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 4 Institute of Health Sciences and Technology, Institutes of Physical Science and Information Technology, Anhui University, Hefei 230601, China.
  • 5 Analysis and Testing Center, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
  • 6 Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
PMID: 42204795 DOI: 10.1021/acs.jmedchem.6c00491
Abstract

BRD9, a distinctive subunit of the ncBAF complex, is a critical regulator of acute myeloid leukemia (AML). Here, we designed, synthesized, and evaluated a series of BRD9 PROTACs. Among them, compound 27 (XYD224) was identified as a highly potent and selective BRD9 Degrader. 27 efficiently induced BRD9 degradation in multiple AML cell lines, including MV4-11, MOLM-13, MOLM-16, Kasumi-1. Mechanistic studies revealed that 27 induces BRD9 degradation in a time-, dose-, CRBN-, and proteasome-dependent manner. Notably, 27 potently inhibited the proliferation of a panel of AML cell lines, with particularly strong activity observed in MV4-11 cells (IC50 = 33 nM). Administration of 27 at 10 and 20 mg/kg (i.p.) achieved tumor growth inhibition (TGI) rates of 70 and 79%, respectively, with a favorable safety profile in the MV4-11 xenograft model. Collectively, these findings underscore the potent preclinical efficacy of 27 and support its advancement as a promising therapeutic candidate for AML.

Figures
Products