Researchers have recently optimized the cereblon (CRBN) ligand and linker moieties to develop two novel, highly selective proteolysis-targeting chimera (PROTAC) degraders, XYD224 and XYD270, providing new candidates for targeting the BRD9 protein in cancer therapy.

The research was led by the Intelligent Drug Design Research Group at the Guangzhou Institutes of Biomedicine and Health (GIBH) of the Chinese Academy of Sciences (CAS).

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 and 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, also displayed exceptionally potent and selective BRD9 degradation in the synovial sarcoma cell line HS-SY-II and the AML cell line MV4-11, while showing 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%.

According to the researchers, this study elucidates a molecular optimization strategy for targeting BRD9 through PROTAC technology and provides candidate molecules with potential for further development in the treatment of synovial sarcoma and acute myeloid leukemia. The discovery of XYD224 and XYD270 also lays a foundation for the further development of antitumor agents targeting the ncBAF complex.