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

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 <b>32 (XYD270)</b> as a highly potent PROTAC demonstrating excellent degradation activity in HS-SY-II cells (DC<sub>50</sub> = 0.082 nM, <i>D</i><sub>max</sub> = 96%) and MV4;11 cells (DC<sub>50</sub> = 3.9 nM, <i>D</i><sub>max</sub> = 90%). Notably, <b>32</b> displayed robust antiproliferative activity in MV4;11 cells (IC<sub>50</sub> = 50 nM) and HS-SY-II cells (IC<sub>50</sub> = 1.65 μM). In an MV4;11 xenograft model, once-daily administration of <b>32</b> (10 mg/kg) achieved significant tumor growth inhibition (TGI = 54%). Taken together, our findings establish <b>32</b> as a promising BRD9 PROTAC with compelling preclinical efficacy in SS and AML.

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Publication Details

Journal
Journal of Medicinal Chemistry
Published
2026-03-04
DOI
https://doi.org/10.1021/acs.jmedchem.5c02858
Primary Topic
Protein Degradation and Inhibitors
Type
article
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0.00
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article

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

Zhiguo Chen, Yan Xu, H. F. Shen, Jinming Ma et al.
Journal of Medicinal Chemistry
Protein Degradation and Inhibitors
article

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

Zhiguo Chen, Yan Xu, H. F. Shen, Jinming Ma, Tingting Xu, Yumin Huang, Di Wu, Guizhen Cheng, Jinsong Liu, Jiankang Hu, Mohan zhao, Bin Lin, Cheng Zhang, Xin Tang
article en

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 <b>32 (XYD270)</b> as a highly potent PROTAC demonstrating excellent degradation activity in HS-SY-II cells (DC<sub>50</sub> = 0.082 nM, <i>D</i><sub>max</sub> = 96%) and MV4;11 cells (DC<sub>50</sub> = 3.9 nM, <i>D</i><sub>max</sub> = 90%). Notably, <b>32</b> displayed robust antiproliferative activity in MV4;11 cells (IC<sub>50</sub> = 50 nM) and HS-SY-II cells (IC<sub>50</sub> = 1.65 μM). In an MV4;11 xenograft model, once-daily administration of <b>32</b> (10 mg/kg) achieved significant tumor growth inhibition (TGI = 54%). Taken together, our findings establish <b>32</b> as a promising BRD9 PROTAC with compelling preclinical efficacy in SS and AML.

Journal of Medicinal ChemistryVol. 69(6)
Shenyang Pharmaceutical University (CN), Anhui University (CN), Guangzhou Institutes of Biomedicine and Health (CN), Drug Discovery Laboratory (Norway) (NO), Biocom (US), University of Chinese Academy of Sciences (CN), University of Pamplona (CO), Guangzhou Medical University (CN)
Good health and well-being
Openalex Percentile: Top 33%
Protein Degradation and Inhibitors
DOISourceOpenAlex
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Discovery of XYD270 as a Potent, Selective, and Orally Efficacious BRD9 PROTAC for Cancer Therapy — Zhiguo Chen, Yan Xu, et al. · Journal of Medicinal Chemistry (2026) | TGRS Research Map | TGRS