Abstract 4515: Orally bioavailable PROTAC based MDM2 degrader

Abstract

Abstract Activation of the tumor suppressor p53, through inhibition of the MDM2 protein, has been pursued as a cancer therapeutic strategy and has produced many distinct inhibitors that are in clinical trials. A limitation arising from inhibiting the MDM2-p53 interaction is the upregulation of MDM2, itself a target gene of p53, and this attenuates the activation of p53 and efficacy of the inhibitors. To circumvent this limitation, we previously reported the first PROTAC based MDM2 degraders. These induced and sustained robust degradation of MDM2, achieved stronger p53 activation, and more potent anticancer activity than MDM2 inhibitors thus representing a new therapeutic strategy for targeting MDM2. Currently, all the PROTAC based MDM2 degraders are all dosed intravenously. Here we describe our design, synthesis, and optimizations that led to the discovery of the first orally bioavailable PROTAC based MDM2 degrader and our investigation of its therapeutic potential and mechanism of action. Consistent with its design to effectively degrade MDM2, our PROTAC effectively induces rapid degradation of MDM2 resulting in accumulation of wild-type p53 protein and activates p53 transcriptional activity in leukemia cells without accumulation of MDM2 protein. Consequently, it potently inhibits cell growth and induces apoptosis at low nano-molar concentrations in ALL and AML cell lines >10-100 times more potent than MDM2 inhibitors; and, after 50 mg/kg oral dose, 5 days/week for 3 weeks, it increased the median survival by 26 days of mice with disseminated RS4;11 cancer. Citation Format: Angelo Aguilar, Jiuling Yang, Yangbing Li, Donna McEachern, Shaomeng Wang. Orally bioavailable PROTAC based MDM2 degrader [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4515.