Fragment-Based Drug Discovery Targeting Inhibitor of Apoptosis Proteins: Discovery of a Non-Alanine Lead Series with Dual Activity Against cIAP1 and XIAP

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• 作者：Gianni Chessari ; Ildiko M. Buck ; James E. H. Day ; Philip J. Day ; Aman Iqbal ; Christopher N. Johnson ; Edward J. Lewis ; Vanessa Martins ; Darcey Miller ; Michael Reader ; David C. Rees ; Sharna J. Rich ; Emiliano Tamanini ; Marc Vitorino ; George A. Ward ; Pamela A. Williams ; Glyn Williams ; Nicola E. Wilsher ; Alison J.-A. Woolford
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：August 27, 2015
• 年：2015
• 卷：58
• 期：16
• 页码：6574-6588
• 全文大小：793K
• ISSN：1520-4804

文摘

Inhibitor of apoptosis proteins (IAPs) are important regulators of apoptosis and pro-survival signaling pathways whose deregulation is often associated with tumor genesis and tumor growth. IAPs have been proposed as targets for anticancer therapy, and a number of peptidomimetic IAP antagonists have entered clinical trials. Using our fragment-based screening approach, we identified nonpeptidic fragments binding with millimolar affinities to both cellular inhibitor of apoptosis protein 1 (cIAP1) and X-linked inhibitor of apoptosis protein (XIAP). Structure-based hit optimization together with an analysis of protein鈥搇igand electrostatic potential complementarity allowed us to significantly increase binding affinity of the starting hits. Subsequent optimization gave a potent nonalanine IAP antagonist structurally distinct from all IAP antagonists previously reported. The lead compound had activity in cell-based assays and in a mouse xenograft efficacy model and represents a highly promising start point for further optimization.