Abstract 470: A MDM2 degrader inhibits cell proliferation and growth of MDM2-overexpressing acute lymphoblastic leukemia in SCID mice

The MDM2 oncogene is amplified and/or overexpressed in various human cancers and elevated expression of MDM2 protein acts as a survival factor promoting cancer progression mainly through inhibition of the tumor suppressor p53. Here, we report a novel small-molecule chemical compound (MX69-114b) that we identified to induce MDM2 protein degradation resulting in reactivation of p53 and potent cell growth inhibition and apoptosis in MDM2-overexpressing acute lymphoblastic leukemia (ALL). We have previously identified a compound (MX69) that binds to the MDM2 C-terminal RING domain and induces MDM2 protein degradation. In the present study, we performed structural modification of MX69 and selected analog MX69-114b showing increased MDM2-targeting activity. MX69-114b exhibited significantly enhanced inhibitory and apoptotic effects on a group of MDM2-overexpressing ALL cell lines in vitro with IC50 values of 0.08-0.14 µM, representing a >80-100-fold increase in activity compared to MX69. MX69-114b also showed inhibitory effects on xenografted human MDM2-overexpressing ALL in SCID mice at a much lower dose than did MX69. Importantly, MX69-114b had minimal or no inhibitory effect on normal human hematopoiesis in vitro and was very well tolerated in vivo in animal models. Based on the strong inhibitory and apoptotic activity against MDM2-overexpressing ALL, along with minimal or no toxicity to normal cells/tissues, MX69-114b is a candidate for further development as a novel MDM2-targeted therapeutic drug for refractory ALL. Citation Format: tao Liu, Lubing Gu, Anna Mui, Zhongzhi Wu, Wei Li, Muxiang Zhou. A MDM2 degrader inhibits cell proliferation and growth of MDM2-overexpressing acute lymphoblastic leukemia in SCID mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 470.