近日，美国Vividion Therapeutics公司Todd M. Kinsella等研究人员合作完成WRN螺旋酶的共价异构抑制剂的化学蛋白组学发掘。2024年4月24日，《自然》杂志在线发表了这项成果。

研究人员介绍了通过化学蛋白质组学发现的处于临床阶段的WRN共价异构抑制剂VVD-133214。这种化合物可选择性地与位于螺旋酶结构域区域的半胱氨酸（C727）结合，该区域在DNA解旋过程中会发生结构域间移动。VVD-133214与核苷酸协同结合WRN蛋白，稳定了缺乏适当螺旋酶功能所需的动态灵活性的紧凑构象，导致微卫星不稳定（MSI）-高（MSI-H）细胞（而非微卫星稳定细胞）出现广泛的双链DNA断裂、核肿胀和细胞死亡。

该化合物在小鼠体内耐受性良好，在多个MSI-H结直肠癌细胞系和患者衍生异种移植模型中可导致肿瘤的显著消退。该工作显示了一种抑制WRN功能的异构方法，它可以规避癌细胞中内源性ATP辅因子的竞争，并将VVD-133214定义为治疗MSI-H癌症患者的一种有前途的候选药物。

据介绍，WRN螺旋酶是治疗MSI癌症的一个前景广阔的靶点，因为它在解决错配修复机制失效的细胞中积累的有害非经典DNA结构方面发挥着至关重要的作用。目前还没有直接靶向人类DNA或RNA螺旋酶的获批药物，部分原因是开发针对这类蛋白的强效选择性化合物具有挑战性。

附：英文原文

Title: Chemoproteomic discovery of a covalent allosteric inhibitor of WRN helicase

Author: Baltgalvis, Kristen A., Lamb, Kelsey N., Symons, Kent T., Wu, Chu-Chiao, Hoffman, Melissa A., Snead, Aaron N., Song, Xiaodan, Glaza, Thomas, Kikuchi, Shota, Green, Jason C., Rogness, Donald C., Lam, Betty, Rodriguez-Aguirre, Maria E., Woody, David R., Eissler, Christie L., Rodiles, Socorro, Negron, Seth M., Bernard, Steffen M., Tran, Eileen, Pollock, Jonathan, Tabatabaei, Ali, Contreras, Victor, Williams, Heather N., Pastuszka, Martha K., Sigler, John J., Pettazzoni, Piergiorgio, Rudolph, Markus G., Classen, Moritz, Brugger, Doris, Claiborne, Christopher, Plancher, Jean-Marc, Cuartas, Isabel, Seoane, Joan, Burgess, Laurence E., Abraham, Robert T., Weinstein, David S., Simon, Gabriel M., Patricelli, Matthew P., Kinsella, Todd M.

Issue&Volume: 2024-04-24

Abstract: WRN helicase is a promising target for treatment of cancers with microsatellite instability (MSI) due to its essential role in resolving deleterious non-canonical DNA structures that accumulate in cells with faulty mismatch repair mechanisms1–5. Currently there are no approved drugs directly targeting human DNA or RNA helicases, in part owing to the challenging nature of developing potent and selective compounds to this class of proteins. Here we describe the chemoproteomics-enabled discovery of a clinical-stage, covalent allosteric inhibitor of WRN, VVD-133214. This compound selectively engages a cysteine (C727) located in a region of the helicase domain subject to interdomain movement during DNA unwinding. VVD-133214 binds WRN protein cooperatively with nucleotide and stabilizes compact conformations lacking the dynamic flexibility necessary for proper helicase function, resulting in widespread double-stranded DNA breaks, nuclear swelling and cell death in MSI-high (MSI-H), but not in microsatellite-stable, cells. The compound was well tolerated in mice and led to robust tumour regression in multiple MSI-H colorectal cancer cell lines and patient-derived xenograft models. Our work shows an allosteric approach for inhibition of WRN function that circumvents competition from an endogenous ATP cofactor in cancer cells, and designates VVD-133214 as a promising drug candidate for patients with MSI-H cancers. VVD-133214, a clinical-stage, covalent allosteric inhibitor of the helicase WRN, was well tolerated in mice and led to robust tumour regression in multiple microsatellite-instability-high colorectal cancer cell lines and patient-derived xenograft models.

DOI: 10.1038/s41586-024-07318-y

Source: https://www.nature.com/articles/s41586-024-07318-y