Gavande Navnath S, VanderVere-Carozza Pamela S, Pawelczak Katherine S, Vernon Tyler L, Jordan Matthew R, Turchi John J
Department of Medicine, Indiana University School of Medicine (IUSM), Indianapolis, Indiana 46202, United States.
Department of Pharmaceutical Sciences, Wayne State University College of Pharmacy and Health Sciences, Detroit, Michigan 48201, United States.
ACS Med Chem Lett. 2020 Jan 2;11(6):1118-1124. doi: 10.1021/acsmedchemlett.9b00440. eCollection 2020 Jun 11.
Replication protein A (RPA) is the major human single stranded DNA (ssDNA)-binding protein, playing essential roles in DNA replication, repair, recombination, and DNA-damage response (DDR). Inhibition of RPA-DNA interactions represents a therapeutic strategy for cancer drug discovery and has great potential to provide single agent anticancer activity and to synergize with both common DNA damaging chemotherapeutics and newer targeted anticancer agents. In this letter, a new series of analogues based on our previously reported TDRL-551 () compound were designed to improve potency and physicochemical properties. Molecular docking studies guided molecular insights, and further SAR exploration led to the identification of a series of novel compounds with low micromolar RPA inhibitory activity, increased solubility, and excellent cellular up-take. Among a series of analogues, compounds , and hold promise for further development of novel anticancer agents.
复制蛋白A（RPA）是主要的人类单链DNA（ssDNA）结合蛋白，在DNA复制、修复、重组及DNA损伤反应（DDR）中发挥着重要作用。抑制RPA与DNA的相互作用是癌症药物研发的一种治疗策略，具有提供单药抗癌活性以及与常见的DNA损伤化疗药物和新型靶向抗癌药物协同作用的巨大潜力。在本信函中，基于我们之前报道的TDRL - 551（ ）化合物设计了一系列新的类似物，以提高其效力和理化性质。分子对接研究提供了分子层面的见解，进一步的构效关系探索导致鉴定出一系列具有低微摩尔RPA抑制活性、增加的溶解度和优异细胞摄取能力的新型化合物。在一系列类似物中，化合物 、 和 有望进一步开发为新型抗癌药物。
