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

Abstract

Activation of p53 by blocking p53-Mdm2 interaction using small-molecule inhibitors is being pursued as a promising cancer therapeutic strategy in p53 wild-type tumors. Here, we report the identification of NVP-HDM201, a novel, highly potent and selective inhibitor of the p53-Mdm2 interaction, with optimized drug-like properties allowing a versatile use with regard to route of administration, dose and scheduling. We determined the pharmacokinetics, pharmacodynamics and efficacy relationship of NVP-HDM201 with various dosing schedules in xenograft bearing mouse and rat models. 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 NVP-HDM201 regimen resulted in a rapid and dramatic induction of p53-dependent PUMA expression and apoptosis. This was consistent with the finding that a single high dose NVP-HDM201 treatment, administered orally or intravenously, resulted in a robust and sustained tumor regression. Overall, both daily and once every 3 weeks dosing regimen showed 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. Citation Format: Stéphane Ferretti, Ramona Rebmann, Marjorie Berger, Francesca Santacroce, Geneviève Albrecht, Kerstin Pollehn, Dario Sterker, Markus Wartmann, Andreas Hueber, Marion Wiesmann, Michael R. Jensen, Francesco Hofmann, William R. Sellers, Philipp Holzer, Sébastien Jeay. 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.

Targeting the Ubiquitin-Proteasome System for Cancer Therapeutics by Small-Molecule Inhibitors

“…HDM201 is an imidazolopyrrolidinone analogue that inhibits the p53–MDM2 interaction [ 202 ] and is currently being subjected to clinical evaluation alone or in combination treatments against various solid or hematological malignancies. Preliminary results reported good bioavailability and induced tumor regression in cancer cell and xenograft animal models [ 131 , 132 ]. Other MDM2 inhibitors currently undergoing clinical studies include APG-115 [ 134 ], APR-246 [ 138 ], and CGM097 [ 136 ].…”

Results from a First-in-Human Phase I Study of Siremadlin (HDM201) in Patients with Advanced Wild-Type TP53 Solid Tumors and Acute Leukemia

“…Siremadlin, an orally bioavailable, selective inhibitor of the p53-MDM2 interaction, has demonstrated single-agent activity in p53 wild-type cell lines and patient-derived xenograft models (18)(19)(20). In pre-clinical models, fractionated low-dose siremadlin induced p21 expression and delayed accumulation of apoptotic cells, while pulsed high-dose siremadlin induced the pro-apoptotic protein PUMA and promoted rapid apoptosis (21).…”

MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer

“…In particular, the optimized interactions of HDM201 with MDM2 protein are responsible for the increased stabilization of the complex leading to a higher potency of the molecule [ 119 ]. In xenograft tumor models, HDM201administration following either a daily low-dose schedule or once at a high-dose schedule induced a differential response; although, the single high-dose schedule lead to rapid and significant induction of P53-dependent PUMA expression and apoptosis together with robust and sustained tumor regression, though the two regimens had an overall comparable long-term efficacy [ 120 ]. There are three ongoing clinical studies aimed to assess and compare different schedules of HDM201 in patients with advanced P53 wild-type tumors (Table 2 ).…”