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. 2014 Oct 15;74(20):5855-65.
doi: 10.1158/0008-5472.CAN-14-0799. Epub 2014 Aug 21.

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

Shaomeng Wang  1 , Wei Sun  2 , Yujun Zhao  2 , Donna McEachern  2 , Isabelle Meaux  3 , Cédric Barrière  3 , Jeanne A Stuckey  4 , Jennifer L Meagher  4 , Longchuan Bai  2 , Liu Liu  2 , Cassandra Gianna Hoffman-Luca  5 , Jianfeng Lu  2 , Sanjeev Shangary  2 , Shanghai Yu  2 , Denzil Bernard  2 , Angelo Aguilar  2 , Odette Dos-Santos  3 , Laurent Besret  3 , Stéphane Guerif  3 , Pascal Pannier  3 , Dimitri Gorge-Bernat  3 , Laurent Debussche  3
Affiliations

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

Shaomeng Wang et al. Cancer Res. .

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 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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Conflict of interest statement

Conflict of interest disclosure statement: MI-77301 has been licensed by Ascenta and Sanofi from the University of Michigan for clinical development and SW, WS, YZ, SS, SY are inventors on the patents and receive royalties. SW owns stock in Ascenta.

Figures

Figure 1
Figure 1
(a). Chemical structures of SAR405838 and MI-219. (b). Affinities of SAR405838 and control compounds to human MDM2 protein, determined in a fluorescence-polarization binding assay. (c). Co-crystal structure of SAR405838/MDM2 at 2.1 Å resolution. (d). Superposition of SAR405838/MDM2 and p53 peptide/MDM2 co-crystal structures.
Figure 2
Figure 2
SAR405838 potently activates p53 in the SJSA-1 and HCT-116 cancer cell lines and strongly induces PUMA up-regulation and cleavage of caspase-3 and PARP in the SJSA-1 cell line but not in the HCT-116 cell line. (a–b). Analysis of dose-dependent transcriptional induction of p21, MDM2 and PUMA in both cell lines. (c–d). Analysis of dose-dependent induction of p53, p21, MDM2 and PUMA proteins and cleavage of caspase-3 and PARP in both cell lines.
Figure 3
Figure 3
SAR405838 induces p53-dependent cell cycle arrest and/or apoptosis in SJSA-1 RS4;11, LNCaP and HCT-116 cancer cell lines. (a). Analysis of apoptosis induction in the four cell lines. (b). Analysis of cell cycle progression in four cell lines. (c). Investigation of the role of p53 in apoptosis induction by SAR405838. (d). Examination of the role of PUMA in apoptosis induction by SAR40583 in the SJSA-1 cell line.
Figure 4
Figure 4
SAR405838 strongly activates p53 and induces apoptosis in SJSA-1 xenograft tumors in mice. (a). qRT-PCT analysis of mRNA induction of MDM2, p21 and PUMA by SAR405838 at different doses and time-points in SJSA-1 tumor tissue. (b). Mesoscale analysis of induction of p53, p21, MDM2, cleaved caspase-3 and cleaved PARP with a single dose of SAR405838 at different doses and time-points in SJSA-1 tumor tissue. (c). Immunohistochemical (IHC) staining of p53 in SJSA-1 tumor tissue. (d). IHC staining of cleaved caspase-3 in SJSA-1 tumor tissue.
Figure 5
Figure 5
SAR405838 induces strong apoptosis and achieves complete tumor regression in the SJSA-1 osteosarcoma xenograft model. (a). Antitumor activity of SAR405838 with daily dosing for 2 weeks. (b). Antitumor activity of a single-dose of SAR405838. (c). FLT-PET imaging analysis of cell proliferation in the SJSA-1 tumor tissue. (d). Enhanced fluorescent Annexin-V imaging uptake analysis of apoptosis in the SJSA-1 tumor tissue.
Figure 6
Figure 6
SAR405838 demonstrates strong antitumor activity in RS4;11, LNCaP and HCT-116 models. (a). Antitumor activity of SAR405838 in the RS4;11 xenograft model. (b). Antitumor activity of SAR405838 in the LNCaP xenograft model. (c). Antitumor activity of SAR405838 in the HCT-116 xenograft model. (d). Enhanced fluorescent Annexin-V imaging uptake analysis of apoptosis in the HCT-116 tumor tissue.
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