5TRF

MDM2 in complex with SAR405838

Summary for 5TRF

• Entry DOI: 10.2210/pdb5trf/pdb
• Descriptor: E3 ubiquitin-protein ligase Mdm2, (2'S,3R,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluorophenyl)-2'-(2,2-dimethylpropyl)-N-(trans-4-hydroxycyclohexyl)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxamide, SULFATE ION, ... (5 entities in total)
• Functional Keywords: p53-binding protein, oncoprotein, double minute 2 protein, small molecule inhibitor, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus, nucleoplasm: Q00987
• Total number of polymer chains: 5
• Total formula weight: 66277.12

Authors

Meagher, J.L.,Stuckey, J.A. (deposition date: 2016-10-26, release date: 2016-11-09, Last modification date: 2024-03-06)

Primary citation

Wang, S.,Sun, W.,Zhao, Y.,McEachern, D.,Meaux, I.,Barriere, C.,Stuckey, J.A.,Meagher, J.L.,Bai, L.,Liu, L.,Hoffman-Luca, C.G.,Lu, J.,Shangary, S.,Yu, S.,Bernard, D.,Aguilar, A.,Dos-Santos, O.,Besret, L.,Guerif, S.,Pannier, P.,Gorge-Bernat, D.,Debussche, L.
SAR405838: an optimized inhibitor of MDM2-p53 interaction that induces complete and durable tumor regression.
Cancer Res., 74:5855-5865, 2014

PubMed Abstract: Blocking the oncoprotein murine double minute 2 (MDM2)-p53 protein-protein interaction has long been considered to offer a broad cancer therapeutic strategy, despite the potential risks of selecting tumors harboring p53 mutations that escape MDM2 control. In this study, we report a novel small-molecule inhibitor of the MDM2-p53 interaction, SAR405838 (MI-77301), that has been advanced into phase I clinical trials. SAR405838 binds to MDM2 with K(i) = 0.88 nmol/L and has high specificity over other proteins. A cocrystal structure of the SAR405838:MDM2 complex shows that, in addition to mimicking three key p53 amino acid residues, the inhibitor captures additional interactions not observed in the p53-MDM2 complex and induces refolding of the short, unstructured MDM2 N-terminal region to achieve its high affinity. SAR405838 effectively activates wild-type p53 in vitro and in xenograft tumor tissue of leukemia and solid tumors, leading to p53-dependent cell-cycle arrest and/or apoptosis. At well-tolerated dose schedules, SAR405838 achieves either durable tumor regression or complete tumor growth inhibition in mouse xenograft models of SJSA-1 osteosarcoma, RS4;11 acute leukemia, LNCaP prostate cancer, and HCT-116 colon cancer. Remarkably, a single oral dose of SAR405838 is sufficient to achieve complete tumor regression in the SJSA-1 model. Mechanistically, robust transcriptional upregulation of PUMA induced by SAR405838 results in strong apoptosis in tumor tissue, leading to complete tumor regression. Our findings provide a preclinical basis upon which to evaluate SAR405838 as a therapeutic agent in patients whose tumors retain wild-type p53.

PubMed: 25145672
DOI: 10.1158/0008-5472.CAN-14-0799

Experimental method

X-RAY DIFFRACTION (2.1 Å)