Abstract 383: Discovery of potent, selective, and orally bioavailable GSPT1 molecular glue degraders (MGDs) for the treatment of MYC-driven tumors

Background: MYC is a well-recognized proto-oncogene, which is mutated and overexpressed in various tumors. However, MYC is challenging to target due to its disordered structure and nuclear localization. There is a significant unmet clinical need for the effective treatments for MYC-driven tumors. G1 to S phase transition 1 (GSPT1) is a translation termination factor regulating protein expression. GSPT1 is involved in many biological processes, including the regulation of cell proliferation, migration, growth cycle and apoptosis. MYC-driven tumors are highly dependent on protein translation to sustain their growth, creating a reliance on the GSPT1 activity. Recent studies have shown that molecular glue degraders (MGDs) targeting GSPT1 affect protein synthesis, thus interfering with the expression of MYC and its downstream target genes. Therefore, GSPT1 is a potential therapeutic target for MYC-driven tumors. Results: Through a comprehensive artificial intelligence-driven drug design and structure-based approach, we designed and synthesized a series of GSPT1 degraders. The most potent degrader effectively degrades GSPT1 proteins in the MDA-MB-468 cells in a dose-dependent manner and achieves a DC50 value of less than 2 nM. The maximum degradation (Dmax) value observed is >95%. The degradation of GSPT1 induced the associated downregulation of MYC (EC50<10 nM), resulting in preferential anti-proliferative activity in MYC-driven cancer cells with IC50 values of 3.28 nM in MDA-MB-468 cells and 0.82 nM in NCI-H1155 cell lines. PK studies revealed low clearance, high plasma exposure, and oral bioavailability in mice. Furthermore, the MGD induced robust and statistically significant tumor growth inhibition (TGI) in the NCI-H1155 and MDA-MB-468 Xenograft Models, with TGI values of 99.57% and 97.93%, respectively. Conclusion: A novel, selective, potent oral GSPT1 degrader was discovered and demonstrated robust anti-tumor activity in mouse xenograft tumor models as a single agent. Collectively, we have identified novel GSPT1 MGDs as promising candidates for the treatment of MYC-driven tumors. Citation Format: Zhimin Zhang, Min Chen, Cancan Cai, Li Teng, Sirui Liu, Yujie Chang, Xinxin Jin, Xiaohua Zhang, Dongzhou Liu. Discovery of potent, selective, and orally bioavailable GSPT1 molecular glue degraders (MGDs) for the treatment of MYC-driven tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 383.