Abstract 1956: Discovery of a novel and potent mutant-selective inhibitor of PI3Kα
Authors: Gao Mingming , Qi Chao , Li Zhentian , Fan Qipeng , Wang Liyang , Zhou Fei , You Lin , Zheng Hewen , Li Yu , Wu Liangxing , Yao Wenqing , Liu Phillip C. 
Published: March 2024

Gain-of-function mutations in hotspots of PI3Kα including H1047R, E545K, and E542K are well-recognized oncogenic drivers in human cancers. Prevalence of these mutations is enriched in many human malignancies, particularly in hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) breast cancer. PI3Kα inhibition showed clear clinical benefit in treating HR+/HER2− breast cancer and has been approved in combination with fulvestrant. First generation PI3Kα inhibitors such as alpelisib and inavolisib, however, have limited selectivity against wild-type (WT) PI3Kα; therefore, are associated with a variety of on-target adverse effects including grade 3 hyperglycemia, skin rash, and gastrointestinal toxicities. Discovery of a highly-selective inhibitor of mutant PI3Kα could enable deeper target coverage while reducing undesired effects of inhibiting WT PI3Kα. SNV-002 is a novel, proprietary, and mutant-selective inhibitor of PI3Kα. In cellular assays, SNV-002 inhibited Ser473 phosphorylation of AKT (pAKT) with single digit nanomolar potency in PI3Kα H1047R-mutant T47D cells and displayed greater than 50-fold selectivity over SKBR3 WT control. Similar inhibition of pAKT was also observed in other cell lines carrying PI3Kα hotspot mutations, such as CAL33, NCI-H1048, EFM19, and HCC1954. SNV-002 maintained selectivity in helical domain E545K-mutant cell lines including MCF7 and MDA-MB-361. This selectivity was further confirmed using MCF10A isogenic cell lines carrying either WT or mutant PI3Kα (H1047R and E545K). In cellular assays to assess inhibition of other isoforms of PI3K (PI3Kβ, PI3Kγ, and PI3Kδ), the IC50 of SNV-002 was over 10,000 nM. Similarly, a broad kinome screen showed no inhibition of activity of 371 kinases. Compared with alpelisib, SNV-002 showed improved potency and prolonged residence time in T47D breast cancer cells. Importantly, assays using H1047R-mutant cells in the presence of human whole blood showed SNV-002 potency to be less than 100 nM, which was over 10-fold more potent than that of alpelisib. Treatment of breast cancer cells with SNV-002 suppressed PI3K-AKT-mTOR pathway, as evidenced by reduced levels of phospho-S6 ribosomal protein and associated with loss of cell viability in mutant lines. The pharmacokinetic profile of SNV-002 was excellent across multiple species. Oral administration of HCC1954 tumor-bearing mice with SNV-002 resulted in dose-proportional exposure and &gt;90% pharmacodynamic inhibition of pAKT in the tumor with doses of 10 mg/kg, and no sign of glucose dysregulation in contrast to alpelisib. Together, these data show that SNV-002 is a highly-selective and potent inhibitor of mutant PI3Kα with good drug-like properties that support further development of SNV-002 for treatment of cancers driven by oncogenic PI3Kα mutations.

Citation Format: Mingming Gao, Chao Qi, Zhentian Li, Qipeng Fan, Liyang Wang, Fei Zhou, Lin You, Hewen Zheng, Yu Li, Liangxing Wu, Wenqing Yao, Phillip C. Liu. Discovery of a novel and potent mutant-selective inhibitor of PI3Kα [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1956.