A Small Molecule Targeting Mutagenic Translesion Synthesis Improves Chemotherapy
A Small Molecule Targeting Mutagenic Translesion Synthesis Improves Chemotherapy
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DOI：
10.1016/j.cell.2019.05.028
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发表时间：
2019-06-27
期刊：
影响因子：
64.5
通讯作者：
Zhou, Pei
中科院分区：
文献类型：
--
作者：
Wojtaszek, Jessica L.;Chatterjee, Nimrat;Zhou, Pei
固有的和获得性的耐药性和继发性恶性肿瘤的诱导限制了成功的化疗。由于诱变跨损伤合成（TLS）有助于化疗耐药性以及治疗诱导的突变，靶向TLS是改善化疗药物的一个有吸引力的途径。然而，开发对致突变TLS具有高特异性和体内功效的小分子一直具有挑战性。在这里，我们报告了一种小分子抑制剂JH-RE-06的发现，该抑制剂通过阻止诱变性POL zeta的募集来破坏诱变性TLS。值得注意的是，JH-RE-06靶向REV 1的几乎无特征的表面，该表面与POL zeta的REV 7亚基相互作用。JH-RE-06的结合诱导REV 1二聚化，其阻断REV 1-REV 7相互作用和POL ζ募集。JH-RE-06在培养的人类和小鼠细胞系中抑制致突变TLS并增强顺铂诱导的毒性。JH-RE-06与顺铂联合给药可抑制小鼠异种移植人黑色素瘤的生长，为开发TLS抑制剂作为新型化疗佐剂建立了框架。
Intrinsic and acquired drug resistance and induction of secondary malignancies limit successful chemotherapy. Because mutagenic translesion synthesis (TLS) contributes to chemoresistance as well as treatment-induced mutations, targeting TLS is an attractive avenue for improving chemotherapeutics. However, development of small molecules with high specificity and in vivo efficacy for mutagenic TLS has been challenging. Here, we report the discovery of a small-molecule inhibitor, JH-RE-06, that disrupts mutagenic TLS by preventing recruitment of mutagenic POL zeta. Remarkably, JH-RE-06 targets a nearly featureless surface of REV1 that interacts with the REV7 subunit of POL zeta. Binding of JH-RE-06 induces REV1 dimerization, which blocks the REV1-REV7 interaction and POL zeta recruitment. JH-RE-06 inhibits mutagenic TLS and enhances cisplatin-induced toxicity in cultured human and mouse cell lines. Co-administration of JH-RE-06 with cisplatin suppresses the growth of xenograft human melanomas in mice, establishing a framework for developing TLS inhibitors as a novel class of chemotherapy adjuvants.