Researchers have developed two PROTAC degraders which target BRD9 for combating malignancies

A research team from the Intelligent Drug Design Research Group at the Guangzhou Institutes of Biomedicine and Health (GIBH) of the Chinese Academy of Sciences has made significant progress in the development of anticancer agents targeting the BRD9 protein. Building upon their previously identified novel BRD9 inhibitor scaffold, the team systematically optimized the CRBN ligand and linker moieties, leading to two novel, highly selective PROTAC degraders, designated XYD224 and XYD270. The findings were published in the Journal of Medicinal Chemistry in two papers entitled "Discovery of a Highly Potent and Efficient BRD9 Degrader with Strong In Vivo Antitumor Activity" and "Discovery of XYD270 as a Potent, Selective, and Orally Efficacious BRD9 PROTAC for Cancer Therapy."

BRD9 is a core component of the non-canonical BAF (ncBAF) chromatin remodeling complex and plays a critical role in the development and progression of various malignancies. In synovial sarcoma, the aberrant incorporation of the SS18-SSX fusion oncoprotein into the cBAF complex renders tumor cells synthetically dependent on ncBAF function, establishing BRD9 as a validated therapeutic target for this disease. In acute myeloid leukemia (AML), BRD9 drives leukemic cell proliferation by upregulating MYC transcription and activating STAT5 signaling. Together, these mechanisms establish BRD9 as a shared oncogenic dependency and a therapeutically valuable target in both refractory malignancies.

Conventional small-molecule BRD9 inhibitors suffer from poor selectivity and limited cellular activity, which have hindered their clinical translation. PROTAC technology, which induces targeted degradation of BRD9 protein, offers a promising strategy to overcome these limitations. In this study, XYD224 demonstrated potent degradation activity in the AML cell line MV4-11, with a DC₅₀ of 7.3 nM and a Dₘₐₓ of 98%, and also exhibited efficient degradation and antiproliferative effects across multiple AML lines, including MOLM-13, MOLM-16, and Kasumi-1. The compound showed no significant degradation of BRD9 homologs or common CRBN substrates, reflecting favorable target selectivity. In an MV4-11 xenograft model, once-daily intraperitoneal administration of XYD224 at 10 mg/kg and 20 mg/kg achieved tumor growth inhibition rates of 70% and 79%, respectively, with no obvious toxicity observed.

The other compound, XYD270, displayed exceptionally potent BRD9 degradation in the synovial sarcoma cell line HS-SY-Ⅱ, with a DC₅₀ of 0.082 nM and a Dₘₐₓ of 96%, and in MV4-11 cells with a DC₅₀ of 3.9 nM and a Dₘₐₓ of 90%. This compound also demonstrated excellent selectivity, with no significant degradation of BRD9 homologs or common CRBN substrates. In vivo, once-daily oral administration of XYD270 at 10 mg/kg significantly suppressed MV4-11 xenograft tumor growth, achieving a tumor growth inhibition rate of 54%.

This study systematically elucidates the molecular optimization strategy for targeting BRD9 via PROTAC technology and provides candidate molecules with substantial clinical translational potential for the treatment of synovial sarcoma and acute myeloid leukemia. The discovery of XYD224 and XYD270 also lays a solid foundation for the further development of antitumor agents targeting the ncBAF complex.

In the study of XYD224, TANG Xin (M.S. candidate) and HUANG Yumin (Ph.D. candidate) from the Intelligent Drug Design Research Group at GIBH contributed equally to this work as co-first authors. Dr. SHEN Hui, Prof. XU Yong, and Prof. ZHANG Yan are the co-corresponding authors of the study. In the study of XYD270, HUANG Yumin (Ph.D. candidate), CHENG Guizhen (M.S. candidate), and TANG Xin (M.S. candidate) are the co-first authors, with Prof. XU Yong, Dr. SHEN Hui, and Prof. LIN Bin serving as the co-corresponding authors.

The study was supported by grants from the National Natural Science Foundation of China, the International Partnership Program of the Chinese Academy of Sciences, and the Guangdong Basic and Applied Basic Research Foundation.

Contacts:

XU Yong, Ph.D., Principal Investigator

Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China, 510530.

Email:xu_yong@gibh.ac.cn