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SAR405838: an optimized inhibitor of MDM2-p53 interaction that induces complete and durable tumor regression

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-molec...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2014-10, Vol.74 (20), p.5855-5865
Main Authors: Wang, Shaomeng, Sun, Wei, Zhao, Yujun, McEachern, Donna, Meaux, Isabelle, Barrière, Cédric, Stuckey, Jeanne A, Meagher, Jennifer L, Bai, Longchuan, Liu, Liu, Hoffman-Luca, Cassandra Gianna, Lu, Jianfeng, Shangary, Sanjeev, Yu, Shanghai, Bernard, Denzil, Aguilar, Angelo, Dos-Santos, Odette, Besret, Laurent, Guerif, Stéphane, Pannier, Pascal, Gorge-Bernat, Dimitri, Debussche, Laurent
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Language:English
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Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-14-0799