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 32 (XYD270) as a highly potent PROTAC demonstrating excellent degradation activity in HS-SY-II cells (DC50 = 0.082 nM, Dmax = 96%) and MV4;11 cells (DC50 = 3.9 nM, Dmax = 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.