Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Road, Unit 3092, Storrs, CT, 06269, USA.
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
ChemMedChem. 2019 Sep 4;14(17):1610-1617. doi: 10.1002/cmdc.201900307. Epub 2019 Aug 21.
Translesion synthesis (TLS) has emerged as a mechanism through which several forms of cancer develop acquired resistance to first-line genotoxic chemotherapies by allowing replication to continue in the presence of damaged DNA. Small molecules that inhibit TLS hold promise as a novel class of anticancer agents that can serve to enhance the efficacy of these front-line therapies. We previously used a structure-based rational design approach to identify the phenazopyridine scaffold as an inhibitor of TLS that functions by disrupting the protein-protein interaction (PPI) between the C-terminal domain of the TLS DNA polymerase Rev1 (Rev1-CT) and the Rev1 interacting regions (RIR) of other TLS DNA polymerases. To continue the identification of small molecules that disrupt the Rev1-CT/RIR PPI, we generated a pharmacophore model based on the phenazopyridine scaffold and used it in a structure-based virtual screen. In vitro analysis of promising hits identified several new chemotypes with the ability to disrupt this key TLS PPI. In addition, several of these compounds were found to enhance the efficacy of cisplatin in cultured cells, highlighting their anti-TLS potential.
跨损伤合成（TLS）已成为一种机制，通过该机制，几种形式的癌症在存在受损 DNA 的情况下允许复制继续进行，从而对一线致瘤化学疗法产生获得性耐药性。抑制 TLS 的小分子有望成为一类新型抗癌药物，可增强这些一线疗法的疗效。我们之前使用基于结构的合理设计方法，确定了苯并恶嗪支架作为 TLS 抑制剂，其通过破坏 TLS DNA 聚合酶 Rev1（Rev1-CT）的 C 末端结构域与其他 TLS DNA 聚合酶的 Rev1 相互作用区（RIR）之间的蛋白质-蛋白质相互作用（PPI）来发挥作用。为了继续鉴定破坏 Rev1-CT/RIR PPI 的小分子，我们基于苯并恶嗪支架生成了一个药效团模型，并在基于结构的虚拟筛选中使用了该模型。对有前途的命中化合物的体外分析确定了几种具有破坏这种关键 TLS PPI 能力的新型化学型。此外，这些化合物中的几种被发现可增强顺铂在培养细胞中的疗效，突出了它们的抗 TLS 潜力。
