Department of Pharmaceutical Sciences, University of Connecticut, 69 N Eagleville Rd, Storrs, CT 06269, USA.
Department of Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, CT 06030, USA.
Bioorg Med Chem. 2018 Aug 7;26(14):4301-4309. doi: 10.1016/j.bmc.2018.07.029. Epub 2018 Jul 19.
Translesion synthesis (TLS) is a DNA damage tolerance mechanism that allows replicative bypass of DNA lesions, including DNA adducts formed by cancer chemotherapeutics. Previous studies demonstrated that suppression of TLS can increase sensitivity of cancer cells to first-line chemotherapeutics and decrease mutagenesis linked to the onset of chemoresistance, marking the TLS pathway as an emerging therapeutic target. TLS is mediated by a heteroprotein complex consisting of specialized DNA polymerases, including the Y-family DNA polymerase Rev1. Previously, we developed a screening assay to identify the first small molecules that disrupt the protein-protein interaction between the C-terminal domain of Rev1 (Rev1-CT) and the Rev1-interacting region (RIR) present in multiple DNA polymerases involved in TLS. Herein we report additional hit scaffolds that inhibit this key TLS PPI. In addition, through a series of biochemical, computational, and cellular studies we have identified preliminary structure-activity relationships and determined initial pharmacokinetic parameters for our original hits.
跨损伤合成（TLS）是一种 DNA 损伤容忍机制，可允许复制体绕过 DNA 损伤，包括由癌症化疗药物形成的 DNA 加合物。先前的研究表明，抑制 TLS 可以提高癌细胞对一线化疗药物的敏感性，并降低与化疗耐药性发生相关的突变，这标志着 TLS 途径是一个新兴的治疗靶点。TLS 由一个异源蛋白复合物介导，该复合物由专门的 DNA 聚合酶组成，包括 Y 家族 DNA 聚合酶 Rev1。此前，我们开发了一种筛选测定法，以鉴定最初的小分子，这些小分子可破坏涉及 TLS 的多个 DNA 聚合酶中的 Rev1 羧基末端结构域（Rev1-CT）与 Rev1 相互作用区（RIR）之间的蛋白-蛋白相互作用。在此，我们报告了抑制该关键 TLS PPI 的其他命中支架。此外，通过一系列生化、计算和细胞研究，我们已经确定了原始命中的初步结构-活性关系，并确定了初始药代动力学参数。
