ZMS-4426

ZMS-4426 is an orally bioavailable small molecule degrader of SMARCA2 (also known as BRM), developed by Simcere Zaiming Pharmaceutical. It is designed to exploit synthetic lethality in SMARCA4-deficient cancers, such as certain types of non-small cell lung cancer (NSCLC). While ZMS-4426 exhibits high potency and selectivity for SMARCA2 over its paralog SMARCA4 in vitro, preclinical studies in multiple species (rats, dogs, and monkeys) have shown a loss of this selectivity in vivo, leading to significant SMARCA4 degradation and associated toxicities. Despite these challenges, ZMS-4426 has demonstrated anti-tumor efficacy in SMARCA4-deficient xenograft models, particularly when used in combination with taxanes like docetaxel or nab-paclitaxel.