Reference Detail

Ref Type

Journal Article

PMID

(25145672)

Authors

Wang S, Sun W, Zhao Y, McEachern D, Meaux I, Barriere C, Stuckey JA, Meagher JL, Bai L, Liu L, Hoffman-Luca CG, Lu J, Shangary S, Yu S, Bernard D, Aguilar A, Dos-Santos O, Besret L, Guerif S, Pannier P, Gorge-Bernat D, Debussche L

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	74	20	2014 Oct 15	5855-65	Cancer Res

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
SAR405838	SAR405838	5	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
SAR405838		MI-77301\|MI-773\|MI773\|SAR-405838	MDM2 Inhibitor 23	SAR405838 (MI-77301) binds to MDM2 and inhibits MDM2-p53 interaction, resulting in activation of wild-type p53 signaling and decreased tumor growth (PMID: 25145672, PMID: 30585255, PMID: 31619389).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
TP53 wild-type	acute leukemia	sensitive	SAR405838	Preclinical - Cell line xenograft	Actionable	In a preclinical study, SAR405838 inhibited growth of TP53 wild-type acute leukemia cells in culture and resulted in tumor regression in cell line xenograft models (PMID: 25145672).	25145672
TP53 wild-type	prostate cancer	sensitive	SAR405838	Preclinical - Cell line xenograft	Actionable	In a preclinical study, SAR405838 inhibited growth of TP53 wild-type prostate cancer cells in culture and resulted in tumor regression in cell line xenograft models (PMID: 25145672).	25145672
TP53 wild-type	colon cancer	sensitive	SAR405838	Preclinical - Cell line xenograft	Actionable	In a preclinical study, SAR405838 inhibited growth of TP53 wild-type colon cancer cells in culture and resulted in tumor regression in cell line xenograft models (PMID: 25145672).	25145672