Abstract 3005: Discovery of a potential therapeutic mechanism for selected tumors via targeting PI3K and DDR pathways simultaneously with a novel orally available small molecule

The genomic instability and hyperactivation of PI3K pathway have been observed in many types of tumors. Targeting some of the key proteins among these pathways such as ATR or mTOR individually has been studied in many clinical trials with various small molecular drug candidates, but so far these efforts have failed to deliver therapeutic benefits to patients. One of the key challenges for targeting these targets is the lack of therapeutic window due to their significant toxicities in clinical trials. It has been evidenced that both PI3K and DDR pathways can be activated simultaneously in many tumor types. We hypothesize that targeting both mTOR and ATR simultaneously could generate synergistic effect to lower the toxicities while maintaining the efficacy in selected tumors. Through rational design, we discovered a novel orally available small molecule LIT-00814 which solely inhibits both mTOR and ATR with great selectivity against other kinases. In preclinical studies, LIT-00814 demonstrates much larger therapeutic window while maintaining good efficacy in selected tumor models with higher DDR mutations and PI3K pathway activities. A specific Akt1-S473 phosphorylation antibody LIT-A0001 has also been developed to precisely stratify patients in clinical trials which is critical to eliminate Akt2 and Akt3 signals and identify right patients for LIT-00814. The clinical phase I trials for LIT-00814 were initiated and the preliminary results hold promise to deliver beneficial therapy to selected cancer patients. In summary, we have discovered a novel orally available small molecule LIT-00814 targeting both mTOR and ATR with novel therapeutic mechanisms of action which could deliver beneficial therapy to selected cancer patients. Citation Format: Wyatt Wei Chen, Wenyu Xu, Yonghui Wang, Zhou Zhou. Discovery of a potential therapeutic mechanism for selected tumors via targeting PI3K and DDR pathways simultaneously with a novel orally available small molecule [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 3005.