5C0L

Fragment-Based Drug Discovery Targeting Inhibitor of Apoptosis Proteins: Compound 2

Summary for 5C0L

• Entry DOI: 10.2210/pdb5c0l/pdb
• Related: 5C0K
• Descriptor: E3 ubiquitin-protein ligase XIAP, ZINC ION, 4-(4-bromo-1H-pyrazol-1-yl)piperidinium, ... (4 entities in total)
• Functional Keywords: ligase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: P98170
• Total number of polymer chains: 1
• Total formula weight: 12982.73

Authors

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. (deposition date: 2015-06-12, release date: 2015-08-12, Last modification date: 2024-05-08)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.6 Å)