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

• Published in: Journal of medicinal chemistry Vol. 58; no. 16; pp. 6574 - 6588
• Main Authors: Chessari, Gianni, Buck, Ildiko M, Day, James E. H, Day, Philip J, Iqbal, Aman, Johnson, Christopher N, Lewis, Edward J, Martins, Vanessa, Miller, Darcey, Reader, Michael, Rees, David C, Rich, Sharna J, Tamanini, Emiliano, Vitorino, Marc, Ward, George A, Williams, Pamela A, Williams, Glyn, Wilsher, Nicola E, Woolford, Alison J.-A
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 27-08-2015
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Cell Proliferation - drug effects; Computational Biology; Drug Design; Drug Discovery; High-Throughput Screening Assays; Humans; Inhibitor of Apoptosis Proteins - antagonists & inhibitors; Inhibitor of Apoptosis Proteins - drug effects; Mice; Mice, Inbred BALB C; Models, Molecular; Peptide Fragments - chemical synthesis; Peptide Fragments - pharmacokinetics; Peptide Fragments - pharmacology; Piperazines - chemical synthesis; Piperazines - pharmacology; X-Linked Inhibitor of Apoptosis Protein - antagonists & inhibitors; Xenograft Model Antitumor Assays
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b00706

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–ligand 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.