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Design and Structure-Guided Development of Novel Inhibitors of the Xeroderma Pigmentosum Group A (XPA) Protein-DNA Interaction.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-09-21 , DOI: 10.1021/acs.jmedchem.7b00780 Navnath S Gavande 1 , Pamela VanderVere-Carozza 1 , Akaash K Mishra 1, 2 , Tyler L Vernon 1 , Katherine S Pawelczak 3 , John J Turchi 1, 2, 3
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-09-21 , DOI: 10.1021/acs.jmedchem.7b00780 Navnath S Gavande 1 , Pamela VanderVere-Carozza 1 , Akaash K Mishra 1, 2 , Tyler L Vernon 1 , Katherine S Pawelczak 3 , John J Turchi 1, 2, 3
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XPA is a unique and essential protein required for the nucleotide excision DNA repair pathway and represents a therapeutic target in oncology. Herein, we are the first to develop novel inhibitors of the XPA-DNA interaction through structure-guided drug design efforts. Ester derivatives of the compounds 1 (X80), 22, and 24 displayed excellent inhibitory activity (IC50 of 0.82 ± 0.18 μM and 1.3 ± 0.22 μM, respectively) but poor solubility. We have synthesized novel amide derivatives that retain potency and have much improved solubility. Furthermore, compound 1 analogs exhibited good specificity for XPA over RPA (replication protein A), another DNA-binding protein that participates in the nucleotide excision repair (NER) pathway. Importantly, there were no significant interactions observed by the X80 class of compounds directly with DNA. Molecular docking studies revealed a mechanistic model for the interaction, and these studies could serve as the basis for continued analysis of structure-activity relationships and drug development efforts of this novel target.
中文翻译：
干燥皮肤色素A组（XPA）蛋白-DNA相互作用的新型抑制剂的设计和结构指导开发。
XPA是核苷酸切除DNA修复途径所需的独特且必不可少的蛋白质，代表肿瘤学中的治疗靶标。在本文中，我们是第一个通过结构导向的药物设计方法开发XPA-DNA相互作用的新型抑制剂的公司。化合物1（X80），22和24的酯衍生物显示出优异的抑制活性（IC50分别为0.82±0.18μM和1.3±0.22μM），但溶解性较差。我们合成了新型的酰胺衍生物，这些衍生物保留了效力并大大提高了溶解度。此外，化合物1类似物对XPA的RPA（复制蛋白A）表现出良好的特异性，RPA是另一种参与核苷酸切除修复（NER）途径的DNA结合蛋白。重要的是，X80类化合物没有直接与DNA发生明显的相互作用。
更新日期：2017-09-21
中文翻译：
干燥皮肤色素A组（XPA）蛋白-DNA相互作用的新型抑制剂的设计和结构指导开发。
XPA是核苷酸切除DNA修复途径所需的独特且必不可少的蛋白质，代表肿瘤学中的治疗靶标。在本文中，我们是第一个通过结构导向的药物设计方法开发XPA-DNA相互作用的新型抑制剂的公司。化合物1（X80），22和24的酯衍生物显示出优异的抑制活性（IC50分别为0.82±0.18μM和1.3±0.22μM），但溶解性较差。我们合成了新型的酰胺衍生物，这些衍生物保留了效力并大大提高了溶解度。此外，化合物1类似物对XPA的RPA（复制蛋白A）表现出良好的特异性，RPA是另一种参与核苷酸切除修复（NER）途径的DNA结合蛋白。重要的是，X80类化合物没有直接与DNA发生明显的相互作用。
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