5C7D

Fragment-Based Drug Discovery Targeting Inhibitor of Apoptosis Proteins: Compound 17

5C7D の概要

• エントリーDOI: 10.2210/pdb5c7d/pdb
• 分子名称: E3 ubiquitin-protein ligase XIAP, ZINC ION, (2R)-4-[2-(6-chloro-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-1-yl)-2-oxoethyl]-2-methylpiperazin-1-ium, ... (4 entities in total)
• 機能のキーワード: ligase, apoptosis
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm: P98170
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 13047.40

構造登録者

Chessari, G.,Buck, I.M.,Day, J.E.H.,Day, P.J.,Iqbal, A.,Johnson, C.N.,Lewis, E.J.,Martins, V.,Miller, D.,Reader, M.,Rees, D.C.,Rich, S.J.,Tamanini, E.,Vitorino, M.,Ward, G.A.,Williams, P.A.,Williams, G.,Wilsher, N.E.,Woolford, A.J.-A. (登録日: 2015-06-24, 公開日: 2015-08-12, 最終更新日: 2024-05-08)

主引用文献

Chessari, G.,Buck, I.M.,Day, J.E.,Day, P.J.,Iqbal, A.,Johnson, C.N.,Lewis, E.J.,Martins, V.,Miller, D.,Reader, M.,Rees, D.C.,Rich, S.J.,Tamanini, E.,Vitorino, M.,Ward, G.A.,Williams, P.A.,Williams, G.,Wilsher, N.E.,Woolford, A.J.
Fragment-Based Drug Discovery Targeting Inhibitor of Apoptosis Proteins: Discovery of a Non-Alanine Lead Series with Dual Activity Against cIAP1 and XIAP.
J.Med.Chem., 58:6574-6588, 2015

PubMed Abstract: 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.

PubMed: 26218264
DOI: 10.1021/acs.jmedchem.5b00706

実験手法

X-RAY DIFFRACTION (2.25 Å)