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

Wang, Shaomeng; Sun, Wei; Zhao, Yujun; McEachern, Donna; Meaux, Isabelle; Barriere, Cedric; 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, Stephane; Pannier, Pascal; Gorge-Bernat, Dimitri; Debussche, Laurent

doi:10.1158/0008-5472.can-14-0799

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

Journal Article · Thu Aug 21 00:00:00 EDT 2014 · Cancer Research

DOI:https://doi.org/10.1158/0008-5472.can-14-0799· OSTI ID:1345500

Wang, Shaomeng ^[1]; Sun, Wei ^[1]; Zhao, Yujun ^[1]; McEachern, Donna ^[1]; Meaux, Isabelle ^[2]; Barriere, Cedric ^[2]; Stuckey, Jeanne A. ^[1]; Meagher, Jennifer L. ^[1]; Bai, Longchuan ^[1]; Liu, Liu ^[1]; Hoffman-Luca, Cassandra Gianna ^[1]; Lu, Jianfeng ^[1]; Shangary, Sanjeev ^[1]; Yu, Shanghai ^[1]; Bernard, Denzil ^[1]; Aguilar, Angelo ^[1]; Dos-Santos, Odette ^[2]; Besret, Laurent ^[2]; Guerif, Stephane ^[2]; Pannier, Pascal ^[2] more »

Univ. of Michigan, Ann Arbor, MI (United States)
Sanofi Oncology, Vitry-sur-Seine (France)

Blocking the 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 nM and has high specificity over other proteins. A co-crystal 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 up-regulation of PUMA induced by SAR405838 results in strong apoptosis in tumor tissue, leading to complete tumor regression. Lastly, 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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Research Organization:: Univ. of Michigan, Ann Arbor, MI (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1345500

Journal Information:: Cancer Research, Vol. 74, Issue 20; ISSN 0008-5472

Publisher:: American Association for Cancer ResearchCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 233 works

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Targeting the MDM2–p53 Protein–Protein Interaction for New Cancer Therapy: Progress and Challenges Wang, Shaomeng; Zhao, Yujun; Aguilar, Angelo Cold Spring Harbor Perspectives in Medicine, Vol. 7, Issue 5 https://doi.org/10.1101/cshperspect.a026245	journal	March 2017
Cellular Senescence: Aging, Cancer, and Injury Calcinotto, Arianna; Kohli, Jaskaren; Zagato, Elena Physiological Reviews, Vol. 99, Issue 2 https://doi.org/10.1152/physrev.00020.2018	journal	April 2019
P53 activation inhibits all types of hematopoietic progenitors and all stages of megakaryopoiesis Mahfoudhi, Emna; Lordier, Larissa; Marty, Caroline Oncotarget, Vol. 7, Issue 22 https://doi.org/10.18632/oncotarget.7881	journal	March 2016
Simultaneous measurement of p53:Mdm2 and p53:Mdm4 protein-protein interactions in whole cells using fluorescence labelled foci Frosi, Y.; Inoue, K.; Ramlan, Siti Radhiah Scientific Reports, Vol. 9, Issue 1 https://doi.org/10.1038/s41598-019-54123-z	journal	November 2019

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