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 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. Our findings provide a preclinical basis upon which to evaluate SAR405838 as a therapeutic agent in patients whose tumors retain wild-type p53.

Early and multiple origins of metastatic lineages within primary tumors

“…Their frequent presence in the root of cancer lineages implies that they play key formative roles in the origin of cancer and that they deserve redoubled attention for their roles in tumorigenesis. The potential to therapeutically target these longstanding drivers of cancer continues to evolve, including targeting TP53 via the TP53/MDM2 interaction (20), targeting KRAS via KRAS G12C (21), targeting posttranslational modifications of KRAS (22), or targeting upstream or downstream effectors (23).…”

Design and Anticancer Activity Prediction of Dihyropyrimidinone Based Novel Inhibitors of P53-Mdm2 Interaction

“…Screening of R/S isomers of ligands L1-L11 provided (S)-L11 as most potent inhibitor of p53-MDM2 interaction. (S)-L11 showed the MDM2 binding pattern similar to that of reference, nutlin-3a and SAR405838 [17,18]. It successfully mimics three crucial residues (Phe19, trp23, and Leu26) of p53 in binding cavity on MDM2 (Fig.…”

Spiro-oxindoles as a Promising Class of Small Molecule Inhibitors of p53–MDM2 Interaction Useful in Targeted Cancer Therapy

“…Spiro(oxindole-3,3 0 -pyrrolidine) emerged as the most potent class of MDM2 inhibitors with high binding affinities to MDM2, cellular potencies, and significantly optimized pharmacokinetic properties. They effectively induced complete tumor regression in the SJSA-1 osteosarcoma xenograft model in mice and have high specificity over other proteins [77]. Various synthetic spiro-oxindoles were identified through structure-based drug design [78].…”

“…The newly developed enantiomer MI-773-01 displayed 10 times higher binding affinity against MDM2 than MI-773 did. The antitumor activity of MI-773-01 (SAR405838) was more pronounced in a set of wild-type p53 xenograft models including osteosarcoma, human prostate, melanoma, colorectal tumor, and acute lymphoblastic leukemia [77]. Compound MI-773-01 (SAR405838) was advanced into phase I clinical trials by Sanofi in 2012 and results showed that the treatment of SJSA-1 osteosarcoma cell lines with SAR405838 in vitro leads to dose-dependent cell growth inhibition, cell cycle arrest, and robust apoptosis [86].…”