Discovery of a Highly Potent and Efficient BRD9 Degrader with Strong In Vivo Antitumor Activity.

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.