ZMS-4084,一种强效且选择性的WRN抑制剂,在MSI-H肿瘤模型中诱导显著的肿瘤消退和持续的完全缓解

Microsatellite instability-high status (MSI-H) is typically prevalent in endometrial, gastrointestinal, ovarian and colorectal cancers. The RecQ helicase WRN has been identified as a synthetic lethal target in MSI-H cancers and represents a promising therapeutic candidate in this context. The two clinical-stage WRN inhibitors, HRO761 and RO7589831, have demonstrated the clinical efficacy in phase I trials. Here we report the discovery of a novel and potent WRN inhibitor, ZMS-4084. Surface plasmon resonance analysis revealed that ZMS-4084 binds specifically to the WRN helicase domain with high affinity (KD=1.08E-08 M). ZMS-4084 selectively inhibited WRN ATPase activity with an IC 50 of 0.05 µM, and exhibited over 2,000-fold selectivity over other RecQ family helicases. Intracellular mechanistic study demonstrated that ZMS-4084 induces apoptosis and inhibits proliferation of HCT116 (MSI-H) cells with an EC 50 of 0.024 µM, accompanied by WRN degradation and accumulation of DNA damage signified by p21 expression and other markers. In a panel of 124 tumor cell lines, ZMD-4084 selectively inhibited the viability of MSI-H cell lines without significant effects on microsatellite stable (MSS) cell lines, indicating high selectivity and a potentially favorable safety profile. Notably, ZMD-4084 effectively suppressed the growth of MSI-H patient-derived organoids, including those previously exposed to standard-of- care therapies such as chemotherapy, anti-EGFR agents, and/or immunotherapy. In vitro ADME and in vivo pharmacokinetics studies demonstrated favorable physicochemical properties and dose-proportional oral bioavailability across preclinical species, supporting its potential for oral administration in humans. Daily administration of ZMS-4084 resulted dose-dependent antitumor efficacy in xenograft models derived from MSI-H human tumors. In the Ishikawa xenograft model, daily dosing at 2.5 mg/kg induced 100% tumor regression, and complete responses (CRs) were achieved in five out of six aminals at 15 mg/kg. Even in the less sensitive RKO xenograft model, 100% tumor regression and several CRs were observed at a dose of 20 mg/kg. No treatment-related abnormalities were observed across all dose regimens in non-GLP preclinical safety studies. In conclusion, we have developed a novel WRN inhibitor, ZMS-4084, which demonstrates robust antitumor activity in both xenograft models and patient-derived organoids representing diverse MSI-H tumor types. Given the synthetic lethality between WRN inhibition and MSI-H status, along with its broad antitumor activity across multiple tumor lineages, ZMS-4084 holds strong potential as a tissue-agnostic therapeutic agent for patients with MSI-H tumors.