ZMS-4426，一种口服SMARCA2降解剂，表现出强效抗肿瘤活性，但在不同物种间对SMARCA4存在选择性差异

Mammalian SWI/SNF complexes always contain one of two mutually exclusive and structurally highly related ATPases: SMARCA2/BRM or SMARCA4/BRG1, as its catalytic subunit. It is reported that SMARCA4 is absent in a serial of cancers, and these SMARCA4 deficient cancer cells are highly dependent on its paralog SMARCA2 for survival. Therefore, it holds great therapeutic promise to treat SMARCA4 deficient cancers with selective SMARCA2 degraders. Here, we reported ZMS-4426, a highly selective SMARCA2 degrader. In HiBiT knock-in HeLa cells, it potently degraded SMARCA2 with a >10,000-fold selectivity over SMARCA4. The global proteome data also indicated that ZMS-4426 was highly specific in degrading the expected target proteins SMARCA2. Furthermore, ZMS-4426 demonstrated high degradation selectivity of SMARCA2 over SMARCA4 in a variety of human cancer cell lines and PBMCs of multiple species. However, in dog PBMCs, the degradation selectivity between SMARCA2 and SMARCA4 varies among individuals.Due to the high selectivity over SMARCA4, ZMS-4426 effectively inhibited the proliferation of SMARCA4 deficient cells, and inhibited the proliferation of neither SMARCA2/4-WT cells nor SMARCA2/4-DEL cells. Furthermore, the in vitro synergistic effects were observed when SMARCA4-loss NSCLC cells were treated with ZMS-4426 in combination with docetaxel.ZMS-4426 exhibited good oral availability in mice, rats, and dog. In the NSCLC NCI-H838 CDX model, ZMS-4426 effectively inhibited tumor growth, and the tumor growth inhibition (TGI) correlated well with SMARCA2 degradation in tumors. Further, the combination treatment of ZMS-4426 and nab-paclitaxel effectively suppressed tumor growth to a greater extent than either agent alone. However, ZMS-4426 was not tolerated in dog for 7-day treatment at 2 mpk. Strong degradation of SMARCA4 in lung was detected, suggesting poor in vivo degradation selectivity in dog. Further, in monkey, the treatment of ZMS-4426 for 7-day at 1.5 mpk resulted in body weight loss and deep degradation of SMARCA4 in PBMCs, indicating that in vitro degradation selectivity in monkey PBMCs did not maintained in vivo .Similar findings were also observed in rats. In a head-to-head comparison with compound A (a reference molecule from WO2025194405, Prelude Therapeutics), treatment of ZMS-4426 and compound A for 4-day at 5 mpk intravenous injection in rats both induced complete degradation of SMARCA4 at 24 hours post-dose, indicating that neither compound preserved its selectivity profile in vivo .In conclusion, our potent and selective SMARCA2 degrader, ZMS-4426 induces strong synthetic lethality in SMARCA4 deficient cells both in vitro and in vivo. However, more studies are needed to elucidate discrepancy in degradation selectivity between in vitro and in vivo results.