SAR405838: A Novel and Potent Inhibitor of the MDM2:p53 Axis for the Treatment of Dedifferentiated Liposarcoma

Abstract

Purpose Dedifferentiated liposarcoma (DDLPS) is an aggressive malignancy that can recur locally or disseminate even after multidisciplinary care. Genetically amplified and expressed MDM2, often referred to as a “hallmark” of DDLPS, mostly sustains a wild-type p53 genotype, substantiating the p53-MDM2 axis as a potential therapeutic target for DDLPS. Here we report on the preclinical effects of SAR405838, a novel and highly selective MDM2 small-molecule inhibitor, in both in vitro and in vivo DDLPS models. Experimental Design The therapeutic effectiveness of SAR405838 was compared to the known MDM2 antagonists Nutlin-3a and MI-219. The effects of MDM2 inhibition were assessed in both in vitro and in vivo. In vitro and in vivo microarray analyses were performed to assess differentially expressed genes induced by SAR405838, as well as the pathways that these modulated genes enriched. Results SAR405838 effectively stabilized p53 and activated the p53 pathway, resulting in abrogated cellular proliferation, cell cycle arrest, and apoptosis. Similar results were observed with Nutlin-3a and MI-219; however, significantly higher concentrations were required. In vitro effectiveness of SAR405838 activity was recapitulated in DDLPS xenograft models where significant decreases in tumorigenicity were observed. Microarray analyses revealed genes enriching the p53 signaling pathway as well as genomic stability and DNA damage following SAR405838 treatment. Conclusion SAR405838 is currently in early phase clinical trials for a number of malignancies, including sarcoma, and our in vitro and in vivo results support its use as a potential therapeutic strategy for the treatment of DDLPS.

Precision Medicine in Soft Tissue Sarcoma Treatment

“…MDM2 and CDK4 were already familiar as important factors in the pathological diagnosis of liposarcoma, but as MDM2-or CDK4-targeted drugs were investigated, their efficacies against STS (especially liposarcomas) were also evaluated. The investigation of MDM2 inhibitors has been limited to preclinical and early-phase trials [68,69], but there are some phase 2 results for CDK4 inhibitors; liposarcomas showed modest responses to them [70,71]. However, the response rates were not high enough to obtain approval for a single-arm phase 2 trial, and further randomized clinical trials are necessary to confirm the clinical efficacies of CDK4 inhibitors.…”

Cooperation of Nutlin-3a and a Wip1 inhibitor to induce p53 activity

“…Since many tumor cells merely arrest in response to Nutlin but resume proliferation once the drug is taken off, the clinical response might be transient at best. One way to get around this problem is to select tumors with a high frequency of Mdm2 amplifications, e. g. dedifferentiated liposarcomas [6, 7]. Another way to fortify the efficacy of Nutlin and related drugs would be to combine them with additional compounds.…”

Virtual Screening Based on Ensemble Docking Targeting Wild‐Type p53 for Anticancer Drug Discovery

“…Because the basal level of p53 is low in HCT116 cells, an extremely low level of luciferase was driven by the basic promoter at the resting state, while enhanced luciferase activities would be detected in response to the increased p53 transcriptional activity in cells. All 181 candidates were evaluated using the high-throughput screening system following the indicated process in Figure 2B, together with MDM2 inhibitor SAR405838 [18] which induced a 3.6-fold increase in luciferase activities. To rule out the potential artificial positive results, compounds inducing changes more than 3.6-fold were believed as positive hits.…”