Design, synthesis and pharmacological evaluation of new SMARCA2 degraders bearing a furo[3,2-c]pyridazine scaffold.

As mutually exclusive catalytic ATPase subunits of the SWI/SNF chromatin remodeling complex, SMARCA2 and SMARCA4 play crucial roles in regulating gene transcription. Studies have revealed that SMARCA4-deficient cells exquisitely depend on SMARCA2 for survival, suggesting SMARCA2 is a promising synthetic lethal target in SMARCA4-deficient cancers. Herein, we reported the design, synthesis, and biological evaluation of a series of novel proteolysis targeting chimeras (PROTACs) of SMARCA2 bearing a novel furo[3,2-c]pyridazine scaffold. Among these compounds, compound 26 displayed an excellent SMARCA2 degradation efficiency with a DC50 value of 51 nM and potently inhibited SMARCA4-deficient cancer cell growth. Compared with AU-15330, which has comparable degradation activity towards SMARCA2/4 (DC50: 42 nM vs 41 nM), compound 26 achieved a 5-fold selectivity towards SMARCA2. In NCI-H1944 xenograft model, 26 significantly reduced SMARCA2 protein levels in tumor tissue and inhibited tumor growth without obvious adverse events, indicating that compound 26 is a promising lead compound for further evaluation as potential treatment of SMARCA4-deficient cancers.