Patrone James D, Pelz Nicholas F, Bates Brittney S, Souza-Fagundes Elaine M, Vangamudi Bhavatarini, Camper Demarco V, Kuznetsov Alexey G, Browning Carrie F, Feldkamp Michael D, Frank Andreas O, Gilston Benjamin A, Olejniczak Edward T, Rossanese Olivia W, Waterson Alex G, Chazin Walter J, Fesik Stephen W
Department of Biochemistry, Vanderbilt University, Nashville, TN, 37232, USA.
Department of Chemistry, Rollins College, 1000 Holt Avenue, Winter Park, FL, 32789, USA.
ChemMedChem. 2016 Apr 19;11(8):893-9. doi: 10.1002/cmdc.201500479. Epub 2016 Jan 8.
Replication protein A (RPA) is an essential single-stranded DNA (ssDNA)-binding protein that initiates the DNA damage response pathway through protein-protein interactions (PPIs) mediated by its 70N domain. The identification and use of chemical probes that can specifically disrupt these interactions is important for validating RPA as a cancer target. A high-throughput screen (HTS) to identify new chemical entities was conducted, and 90 hit compounds were identified. From these initial hits, an anthranilic acid based series was optimized by using a structure-guided iterative medicinal chemistry approach to yield a cell-penetrant compound that binds to RPA70N with an affinity of 812 nm. This compound, 2-(3- (N-(3,4-dichlorophenyl)sulfamoyl)-4-methylbenzamido)benzoic acid (20 c), is capable of inhibiting PPIs mediated by this domain.
复制蛋白A（RPA）是一种必需的单链DNA（ssDNA）结合蛋白，它通过其70N结构域介导的蛋白质-蛋白质相互作用（PPI）启动DNA损伤反应途径。鉴定和使用能够特异性破坏这些相互作用的化学探针对于验证RPA作为癌症靶点至关重要。我们进行了一次高通量筛选（HTS）以鉴定新的化学实体，并鉴定出90种活性化合物。从这些初始活性化合物中，通过使用结构导向的迭代药物化学方法优化了基于邻氨基苯甲酸的系列，以产生一种细胞渗透性化合物，该化合物以812 nm的亲和力与RPA70N结合。这种化合物，2-（3-（N-（3,4-二氯苯基）磺酰基）-4-甲基苯甲酰胺基）苯甲酸（20 c），能够抑制由该结构域介导的PPI。
