Cancers with microsatellite instability (MSI) are defined by the accumulation of insertion and/or deletion mutations in microsatellites due to loss of DNA mismatch repair activity. Synthetic lethal genetic screens previously identified a dependence of MSI on the Werner syndrome RecQ helicase WRN, which normally ensures the maintenance of genomic stability and DNA repair. Genetic inhibition of WRN in MSI cancers results in DNA damage, cell death and decreased tumor growth, suggesting a potential druggable target. Baltgalvis et al. have now used a mass spectrometry-based chemoproteomics approach to enable the identification of covalent, allosteric molecules that selectivity engage C727 on WRN and that were optimized to provide VVD-133214. In a second paper, Ferretti et al. developed an ATP-binding screen to identify a non-covalent inhibitor of WRN activity with medicinal chemistry optimization revealing HRO761 as the most active compound. Crystal structures of WRN in complex with the inhibitors showed binding at a non-conserved site at the interface of the D1/D2 helicase domain to trap WRN in an inactive conformation. HRO761 and VVD-133214 were selectively cytotoxic in MSI-H cells, inducing DNA damage and cell cycle arrest while sparing microsatellite-stable cancer cells. Both compounds exhibited good physicochemical, pharmacokinetic and target engagement properties and limited toxicity. Treatment with either inhibitor reduced MSI-H and patient-derived mouse xenograft tumor growth through increased DNA damage. The combination of HRO761 and irinotecan, an inhibitor of DNA topoisomerase I, exhibited enhanced effects in vitro and in vivo while VVD-133214 was active in MSI-H tumors that are immunotherapy resistant. Overall, the work from Baltgalvis et al. and Ferretti et al. revealed a potential therapeutic for MSI cancers.

Original references: Nature 629, 435–442 (2024); Nature 629, 443–449 (2024)

微卫星不稳定性 (MSI) 癌症的定义是由于 DNA 错配修复活性丧失而导致微卫星中插入和/或缺失突变的积累。合成致死基因筛查先前发现 MSI 对维尔纳综合征 RecQ 解旋酶 WRN 的依赖性，该酶通常确保基因组稳定性和 DNA 修复的维持。在 MSI 癌症中对 WRN 进行基因抑制会导致 DNA 损伤、细胞死亡和肿瘤生长减少，这表明它是一个潜在的药物靶标。巴尔特加尔维斯等人。现在已经使用基于质谱的化学蛋白质组学方法来识别共价变构分子，这些分子选择性地与 WRN 上的 C727 结合，并经过优化以提供 VVD-133214。在第二篇论文中，Ferretti 等人。开发了一种 ATP 结合筛选，通过药物化学优化来鉴定 WRN 活性的非共价抑制剂，显示 HRO761 是最活跃的化合物。 WRN 与抑制剂复合物的晶体结构显示，在 D1/D2 解旋酶结构域界面的非保守位点处结合，将 WRN 捕获在非活性构象中。 HRO761 和 VVD-133214 在 MSI-H 细胞中具有选择性细胞毒性，诱导 DNA 损伤和细胞周期停滞，同时不影响微卫星稳定的癌细胞。两种化合物均表现出良好的理化、药代动力学和靶标结合特性以及有限的毒性。使用任一抑制剂治疗可通过增加 DNA 损伤来减少 MSI-H 和患者来源的小鼠异种移植肿瘤的生长。 HRO761 和 DNA 拓扑异构酶 I 抑制剂伊立替康的组合在体外和体内表现出增强的效果，而 VVD-133214 在免疫治疗耐药的 MSI-H 肿瘤中具有活性。总的来说，Baltgalvis 等人的工作。和费雷蒂等人。 揭示了 MSI 癌症的潜在治疗方法。

原始参考文献： Nature 629 , 435–442 (2024)；自然629 , 443–449 (2024)