5OQW

XIAP in complex with small molecule

Summary for 5OQW

• Entry DOI: 10.2210/pdb5oqw/pdb
• Descriptor: E3 ubiquitin-protein ligase XIAP, ZINC ION, SODIUM ION, ... (5 entities in total)
• Functional Keywords: xiap, protease inhibitor, apoptosis regulation, apoptosis
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 30385.79

Authors

Williams, P.A. (deposition date: 2017-08-14, release date: 2018-06-27, Last modification date: 2024-05-08)

Primary citation

Ward, G.A.,Lewis, E.J.,Ahn, J.S.,Johnson, C.N.,Lyons, J.F.,Martins, V.,Munck, J.M.,Rich, S.J.,Smyth, T.,Thompson, N.T.,Williams, P.A.,Wilsher, N.E.,Wallis, N.G.,Chessari, G.
ASTX660, a Novel Non-peptidomimetic Antagonist of cIAP1/2 and XIAP, Potently Induces TNF alpha-Dependent Apoptosis in Cancer Cell Lines and Inhibits Tumor Growth.
Mol. Cancer Ther., 17:1381-1391, 2018

PubMed Abstract: Because of their roles in the evasion of apoptosis, inhibitor of apoptosis proteins (IAP) are considered attractive targets for anticancer therapy. Antagonists of these proteins have the potential to switch prosurvival signaling pathways in cancer cells toward cell death. Various SMAC-peptidomimetics with inherent cIAP selectivity have been tested clinically and demonstrated minimal single-agent efficacy. ASTX660 is a potent, non-peptidomimetic antagonist of cIAP1/2 and XIAP, discovered using fragment-based drug design. The antagonism of XIAP and cIAP1 by ASTX660 was demonstrated on purified proteins, cells, and in xenograft models. The compound binds to the isolated BIR3 domains of both XIAP and cIAP1 with nanomolar potencies. In cells and xenograft tissue, direct antagonism of XIAP was demonstrated by measuring its displacement from caspase-9 or SMAC. Compound-induced proteasomal degradation of cIAP1 and 2, resulting in downstream effects of NIK stabilization and activation of noncanonical NF-κB signaling, demonstrated cIAP1/2 antagonism. Treatment with ASTX660 led to TNFα-dependent induction of apoptosis in various cancer cell lines , whereas dosing in mice bearing breast and melanoma tumor xenografts inhibited tumor growth. ASTX660 is currently being tested in a phase I-II clinical trial (NCT02503423), and we propose that its antagonism of cIAP1/2 and XIAP may offer improved efficacy over first-generation antagonists that are more cIAP1/2 selective. .

PubMed: 29695633
DOI: 10.1158/1535-7163.MCT-17-0848

Experimental method

X-RAY DIFFRACTION (2.31 Å)