SAR405838: An Optimized Inhibitor of MDM2–p53 Interaction That Induces Complete and Durable Tumor Regression
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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 Ki = 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. Cancer Res; 74(20); 5855–65. ©2014 AACR.
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In the SJSA-1 model, SAR-405838 effectively inhibited the growth of tumor cell lines and induced apoptosis in ABTR1 and ABTR2 sublines in a dose-dependent manner.
“In the SJSA-1 model, SAR-405838 effectively inhibited the growth of tumor cell lines and induced apoptosis in ABTR1 and ABTR2 sublines in a dose-dependent manner.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [381]
SAR-405838 is a spiroxindole-based MDM2 inhibitor that demonstrates strong binding affinity to MDM2 and effective growth inhibition activity.
“SAR-405838 (143) is a spiroxindole-based MDM2 inhibitor that demonstrates strong binding affinity to MDM2 and effective growth inhibition activity.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [381]
SAR-405838 has shown high selectivity for cancer cell lines with mutations or deletions of p53.
“It has shown high selectivity for cancer cell lines with mutations or deletions of p53.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [381]
In mouse xenograft models of SJSA1, RS411, LNCaP, and HCT-116, SAR-405838 achieved lasting tumor regression or complete inhibition of tumor growth under a well-tolerated dose regimen.
“In mouse xenograft models of SJSA1, RS411, LNCaP, and HCT-116, SAR-405838 achieved lasting tumor regression or complete inhibition of tumor growth under a well-tolerated dose regimen.381,382”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [381]
Inhibition of the MDM2-p53 interaction restores p53 activity and leads to cell cycle arrest and apoptosis.
“Inhibition of the MDM2-p53 interaction restores p53 activity and leads to cell cycle arrest and apoptosis.”
From Restoration of p53 using the novel MDM2-p53 antagonist APG115 suppresses dedifferentiated papillary thyroid cancer cells (2017) · cites this paper as [19]
SAR405838 can lead to durable tumor regression by complete tumor growth inhibition in SJSA-1, RS4;11, LNCaP and HCT-116 xenograft models.
“In well-tolerated dose regimens, SAR405838 can lead to durable tumor regression by complete tumor growth inhibition in SJSA-1, RS4;11, LNCaP and HCT-116 xenograft models.”
From Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials (2022) · cites this paper as [40]
MI-77301 (SAR405838) binding activity with MDM2 reached 0.88 nM, with high selectivity and high specificity over other proteins.
“MI-77301 (SAR405838) was obtained by simply replacing the groups exposed to the solvent region of MI-888, and its binding activity with MDM2 reached 0.88 nM, with a high selectivity and high specificity over other proteins [40].”
From Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials (2022) · cites this paper as [40]
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- Authors
- Wang, S., Sun, W., Zhao, Y., McEachern, D., Meaux, I., Barrière, 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.
- Affiliations
- University of Michigan (US)
- Sanofi (France) (FR)
- 1University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
- 5Sanofi Oncology, Vitry-sur-Seine, France.
- Corresponding author
- Wang, Shaomeng
- ORCID
- Venue
- Cancer Research
- Published
- 2014-10-14
- Volume
- 74
- Issue
- 20
- Pages
- 5855-5865
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC4247201
- OpenAlex
- W2055551025
- Cited by
- 328
- References
- 42
- Citations by year
- 2026: 8 · 2025: 29 · 2024: 21 · 2023: 25 · 2022: 26 · 2021: 43 · 2020: 30 · 2019: 34 · 2018: 29 · 2017: 26 · 2016: 31 · 2015: 20 · 2014: 6
- FWCI
- 14.17
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- U.S. Department of Energy (DE‐ AC02‐06CH11357, AC02‐06CH11357, 085P1000817, 06CH11357, DE-AC02-)
- Sanofi
- National Institutes of Health (DE-AC02–06CH11357, 085P1000817)
- Michigan Technology Tri-Corridor (DE-AC02-06CH11357, 085P1000817)
- National Cancer Institute (R01CA121279, P50CA069568, P30CA046592, P50CA186786)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- p53-MDM2 interaction, small molecule inhibitors, p53 activation, co-crystal structure, PUMA, apoptosis, cell cycle arrest, tumor regression, osteosarcoma, acute leukemia, prostate cancer, colon cancer, xenograft models
- MeSH terms
- Animals, Antineoplastic Agents, Dogs, Drug Stability, Humans, Indoles, Protein Binding, Proto-Oncogene Proteins, Remission Induction, Spiro Compounds, Tumor Suppressor Protein p53, Apoptosis, Xenograft Model Antitumor Assays, HCT116 Cells, Cell Proliferation, Apoptosis Regulatory Proteins, Mice, Rats, Proto-Oncogene Proteins c-mdm2, Cell Cycle Checkpoints
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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