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

Abstract

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 bymore » 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.« less

Authors:
 [1];  [1];  [1];  [1];  [2];  [2];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [2];  [2];  [2];  [2] more »;  [2];  [2] « less
  1. Univ. of Michigan, Ann Arbor, MI (United States)
  2. Sanofi Oncology, Vitry-sur-Seine (France)
Publication Date:
Research Org.:
Univ. of Michigan, Ann Arbor, MI (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1345500
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Cancer Research
Additional Journal Information:
Journal Volume: 74; Journal Issue: 20; Journal ID: ISSN 0008-5472
Publisher:
American Association for Cancer Research
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; MDM2; p53; small-molecule inhibitor; protein-protein interaction

Citation Formats

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, and Debussche, Laurent. SAR405838: An optimized inhibitor of MDM2-p53 interaction that induces complete and durable tumor regression. United States: N. p., 2014. Web. doi:10.1158/0008-5472.can-14-0799.
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. SAR405838: An optimized inhibitor of MDM2-p53 interaction that induces complete and durable tumor regression. United States. doi:10.1158/0008-5472.can-14-0799.
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, and Debussche, Laurent. Thu . "SAR405838: An optimized inhibitor of MDM2-p53 interaction that induces complete and durable tumor regression". United States. doi:10.1158/0008-5472.can-14-0799. https://www.osti.gov/servlets/purl/1345500.
@article{osti_1345500,
title = {SAR405838: An optimized inhibitor of MDM2-p53 interaction that induces complete and durable tumor regression},
author = {Wang, Shaomeng and Sun, Wei and Zhao, Yujun and McEachern, Donna and Meaux, Isabelle and Barriere, Cedric and Stuckey, Jeanne A. and Meagher, Jennifer L. and Bai, Longchuan and Liu, Liu and Hoffman-Luca, Cassandra Gianna and Lu, Jianfeng and Shangary, Sanjeev and Yu, Shanghai and Bernard, Denzil and Aguilar, Angelo and Dos-Santos, Odette and Besret, Laurent and Guerif, Stephane and Pannier, Pascal and Gorge-Bernat, Dimitri and Debussche, Laurent},
abstractNote = {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 Ki = 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.},
doi = {10.1158/0008-5472.can-14-0799},
journal = {Cancer Research},
number = 20,
volume = 74,
place = {United States},
year = {Thu Aug 21 00:00:00 EDT 2014},
month = {Thu Aug 21 00:00:00 EDT 2014}
}

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