Abstract LB437: LAE118, a pan mutant-selective PI3Ka inhibitor with superb activity against both the kinase domain and helical domain mutants

Abstract PIK3CA is one of the most frequently mutated oncogenes - found in 15-30% of all cancers, particularly prevalent in patients with breast, colorectal, endometrial, and various other cancers. Three hotspot mutations on the p110α subunit of PI3Ka (H1047R in the kinase domain and E545K, E542K in the helical domain) are recognized activating mutations accounting for more than 1/3 of all PI3Ka mutations. In response to this, pan-mutant selective PI3Ka inhibitors including RLY-2608 and STX-478 are being developed in clinical trials for cancer patients with PIK3CA mutations. By sparing wild type PI3Ka, these inhibitors demonstrated improved therapeutic window compared with orthosteric PI3Ka inhibitors and maintained good clinical responses for the kinase domain mutants. However, due to relatively weak potency against PIK3CA helical domain mutants, these two inhibitors have less favorable clinical responses in patients harboring this type of mutations. Therefore, there is a pressing need to develop novel pan-mutant selective PI3Ka inhibitors with improved activity against helical domain mutants to expand treatment options for a broader patient population.LAE118 is a promising novel allosteric pan-mutant selective PI3Ka inhibitor demonstrating excellent in vitro anti-proliferation activities against both kinase and helical domain mutant cells. Preclinical studies revealed that LAE118 effectively inhibits tumor growth in Xenograft models, including GP2D (H1047L), HCC1954 (H1047R), MCF7 (E545K) and MDA-MB-361 (E545K) at doses that are much lower than other pan-mutant selective PI3Ka inhibitors. Additionally, LAE118 exhibits strong efficacy in patient-derived xenograft (PDX) models. Importantly, LAE118 has clean profiles in the kinase panel and in the secondary pharmacology panel, and balanced PK profiles with low clearance and good oral bioavailability across animal species. Human PK projection indicates LAE118 has the potential to achieve continuous inhibition of pAKT in clinic without causing hyperglycemia. LAE118 is currently in IND enabling stage, positioning it as a promising candidate for the treatment of cancers with PIK3CA mutations. Citation Format: Ming Li, Ruipeng Zhang, Meijuan Hu, Junyan Chen, Xiaofen Lin, Justin Gu. LAE118, a pan mutant-selective PI3Ka inhibitor with superb activity against both the kinase domain and helical domain mutants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB437.