がん治療向けBRD9標的PROTAC分解剤を開発（Researchers Develop Two BRD9-Targeting PROTAC Degraders for Cancer Therapy）

2026-07-21 中国科学院（CAS）

＜関連情報＞

• https://english.cas.cn/newsroom/research-news/202607/t20260721_1178863.shtml
• https://pubs.acs.org/doi/10.1021/acs.jmedchem.6c00491
• https://pubs.acs.org/doi/10.1021/acs.jmedchem.5c02858

強力な生体内抗腫瘍活性を有する、非常に強力かつ効率的なBRD9分解剤の発見 Discovery of a Highly Potent and Efficient BRD9 Degrader with Strong In Vivo Antitumor Activity

Xin Tang,Yumin Huang,Cheng Zhang,Yi Sun,Qingqing Hu,Guizhen Cheng,Jiankang Hu,Zhiming Chen,Xiaohan Zhang,Xiaoxi Zhuang,Adam V. Patterson,Jeff B. Smaill,Xishan Wu,Yan Zhang,Yong Xu,and Hui Shen
Journal of Medical Chemistry  Published: May 27, 2026
DOI:https://doi.org/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.

がん治療のための強力かつ選択的で経口投与可能なBRD9 PROTACであるXYD270の発見 Discovery of XYD270 as a Potent, Selective, and Orally Efficacious BRD9 PROTAC for Cancer Therapy

Yumin Huang,Guizhen Cheng,Xin Tang,Zhiming Chen,Cheng Zhang,Jiankang Hu,Xiaoshan Chen,Jun Wang,Zhaoming Chen,Mohan Zhao,Jinsong Liu,Tingting Xu,Jinming Ma,Yan Zhang,Bin Lin,Hui Shen,and Yong Xu
Journal of Medical Chemistry  Published: March 4, 2026
DOI:https://doi.org/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, D_max = 96%) and MV4;11 cells (DC₅₀ = 3.9 nM, D_max = 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.