Abstract 1673: Discovery of potent, selective, and orally bioavailable GSPT1 degraders and their pre-clinical anti-tumor activity in acute myeloid leukemia and solid tumors

Abstract

Abstract Molecular glue degraders (MGDs) of neo-substrates that function by hijacking the CRBN E3 ligase are clinically validated as therapeutics for the treatment of hematological malignancies. Novel MGDs of GSPT1, a translation termination factor, elicit dysregulated protein translation termination and subsequent induction of TP53-independent apoptosis in acute myeloid leukemia (AML) cells through activation of the integrated stress response. In addition, dysregulation of translation termination triggered by GSPT1 degradation appears to be cytotoxic specifically to MYC-driven cancers including solid tumors with translational addiction. Phase 1 clinical trials of three novel GSPT1 MGDs have been recently launched for the treatment of AML and/or MYC-driven solid tumors (NCT02848001, NCT04336982, NCT05546268, and NCT05144334). Herein, we present novel GSPT1 MGDs and their pre-clinical results against AML and solid tumors. Our current lead GSPT1 MGDs induced rapid, potent, and durable degradation of GSPT1, resulting in strong inhibition of tumor cell growth in a variety of cell lines of MYC-driven solid tumor and blood cancer (AML and acute lymphoblastic leukemia). Moreover, in ex-vivo assays using a panel of patient-derived primary AML cells, C-10386 was highly sensitive with EC50s at the nanomolar range. Furthermore, a related analogue (C-14207) showed excellent rodent PK profiles and demonstrated dose-dependent PKPD relationship and excellent efficacy in the NCI-H1155 NSCLC xenograft model. Finally, our current lead compounds showed safer profiles in various normal cells compared to other known GSPT1 degraders. Collectively, we have identified novel GSPT1 MGDs as promising development candidates for the treatment of AML and solid tumors. Citation Format: Min Sung Joo, JaeYung Lee, Eun-Jung Kim, Dong Hyuk Ki, Hunmi Choi, Joonwoo Nam, Jaewoo Park, Keon Wook Kang, Wooseok Han. Discovery of potent, selective, and orally bioavailable GSPT1 degraders and their pre-clinical anti-tumor activity in acute myeloid leukemia and solid tumors [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 1673.