Abstract 4870: Targeted MDM2 degradation as a novel and efficacious cancer therapy

The E3 ubiquitin ligase MDM2 (Murine Double Minute 2) is the most important negative regulator of p53 tumor suppressor primarily by targeting it for ubiquitination and proteasomal degradation. Amplification or overexpression of the MDM2 gene occurs in many human cancers contributing to tumor development, progression and metastasis. Targeting MDM2 to restore p53 function has become an attractive therapeutic strategy for cancers harboring wild-type TP53. Currently, numerous drugs inhibiting the MDM2-p53 interaction, such as RG7112 (Hoffmann-La Roche), MI-773 (Sanofi) and DS-3032b (Daiichi Sankyo), have entered different stages of clinical trials. However, even in p53 wild-type tumors, MDM2 inhibitors can exert limited efficacy as monotherapy in some models, probably due to inadequate p53 induction and side effects. Therefore novel and improved strategies to effectively target the MDM2-p53 pathway are needed. Recently, we have designed a series of MDM2 degraders by conjugating a small molecule MDM2 inhibitor to phthalimide. The phthalimide moiety interacts with its target protein Cereblon (CRBN) and recruits the CUL4-DDB1-CRBN (also known as CRL4 CRBN ) E3 ubiquitin ligase complex to promote ubiquitination and proteasome degradation of MDM2. Our initial evaluation focused on acute leukemias that are mostly p53 wild-type and express high levels of MDM2. The MDM2 degraders exert significantly improved growth inhibitory activity compared to the inhibitor in human acute leukemia cell lines with IC50s Citation Format: Jiuling Yang, Yangbing Li, Angelo Aguilar, Donna McEachern, Sally Przybranowski, Ester Fernandez-Salas, Jianfeng Lu. Targeted MDM2 degradation as a novel and efficacious cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4870.