Siremadlin, Inhibitor

Siremadlin

Cat. Num. AAA5764901

• Synonyms: Siremadlin; NVP-HDM 201; inhibitor

• Form/Format: Solid

• Solubility: DMSO: 56.75mg/mL (102.18mM); (<1mg/ml refers to the product slightly soluble or insoluble)
• SMILES: CC(C)n1c(-c(cnc(OC)n2)c2OC)nc(C2=O)c1[C@H](c(cc1)ccc1Cl)N2C1=CC(Cl)=CN(C)C1=O
• Formula: C26H24Cl2N6O4
• In vitro: Tumors are allografted in large cohorts of mice to assess the pharmacologic effects of Siremadlin (NVP-HDM201). Sixteen out of 21 allograft models are sensitive to Siremadlin (NVP-HDM201) but ultimately relapse under treatment[1]. Siremadlin has recently entered Phase 1 clinical trials in cancer patients[2]. Siremadlin (NVP-HDM201) administered either daily at a low dose or once at a high dose revealed a differentiated engagement of the p53 molecular response. In contrast to the daily low dose treatment regimen, the single high dose Siremadlin (NVP-HDM201) regimen results in a rapid and dramatic induction of p53-dependent PUMA expression and apoptosis. This is consistent with the finding that a single high dose Siremadlin (NVP-HDM201) treatment, administered orally or intravenously, results in a robust and sustained tumor regression. Overall, both daily and once every 3 weeks dosing regimen shows comparable long term efficacy in preclinical studies. The ongoing clinical trial is currently designed to compare both dosing regimens with regard to efficacy and tolerability[3].
• CAS Number: 1448867-41-1
• Preparation and Storage: Store at 0-4 degree C for short term (days to weeks), or -20 degree C for long term (months).

Chemical Structure

Related Product Information for Siremadlin, inhibitor

Siremadlin is a potent, orally bioavailable and highly specific p53-MDM2 interaction inhibitor.

Product Categories/Family for Siremadlin, inhibitor

Apoptosis; Mdm2

References

Chapeau EA, et al. Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf-/- mouse model. Proc Natl Acad Sci U S A. 2017 Mar 21;114(12):3151-3156.
Furet P, et al. Discovery of a novel class of highly potent inhibitors of the p53-MDM2 interaction by structure-based design starting from a conformational argument. Bioorg Med Chem Lett. 2016 Oct 1;26(19):4837-41.
Stephane F, et al. Abstract 1224: Insights into the mechanism of action of NVP-HDM201, a differentiated and versatile Next-Generation small-molecule inhibitor of Mdm2, under evaluation in phase I clinical trials. Insights into the mechanism of action of NVP-HDM201, a differentiated and versatile Next-Generation small-molecule inhibitor of Mdm2, under evaluation in phase I clinical trials. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1224.