Abstract 5130: Identification and characterization of pan-mutant selective PI3Kα inhibitors with the capability of PI3Kα H1047R protein degradation

Abstract Introduction: PIK3CA, a PI3K isoform, is one of the most frequently mutated genes in human cancers. PIK3CA mutations are highly enriched at “hotspot” sites in the helical (E542K, E545K) and kinase (H1047R/L) domains. Orthosteric inhibitors of PI3Kα, such as alpelisib and inavolisib, have been approved for the treatment of patients with advanced HR+/HER2− breast cancer. Selective targeting of mutant PI3Kα is anticipated to enhance antitumor efficacy and mitigate the toxicity associated with wild-type PI3Kα inhibition in normal tissue. Allosteric and mutant-selective PI3Kα inhibitors, including RLY-2608 (NCT06982521) and LY4064809 (STX-478, NCT07174336), have been successfully developed in the clinical phase III stage. Results: Several allosteric and potent pan-mutant PI3Kα inhibitors developed by TYK Medicines exhibited high selectivity over wild-type (WT) PI3Kα. Our observations revealed that the compounds inhibited AKT phosphorylation in the T47D (PI3Kα H1047R) cell line with an IC50 in the single-digit nanomolar range, demonstrating nearly 200 times more selectivity compared to SK-BR-3 (PI3Kα WT) cells at same time. In in vitro antiproliferative assays, the compounds displayed superior antiproliferative activity against various PI3Kα mutant cells, including T47D, HCC1954 (PI3Kα H1047R), and MCF7 (PI3Kα E545K), compared to STX-478 and RLY-2608. For instance, TY-3659 was four and thirteen times more selective in T47D and MCF7 cells, respectively, than RLY-2608, aligning with the PI3Kα kinase inhibition assays. In addition, TY-3659 effectively degraded PI3Kα mutant protein in HCC1954 and MDA MB 453 (PI3Kα H1047R) cells. In the mouse HCC1954 and Cal33 (PI3Kα H1047R) CDX models, the compounds exhibited potent tumor-inhibitory activity, excellent tolerance, good DMPK properties, and desirable drug-like characteristics. No effects on fasting plasma glucose levels were observed after four days of treatment in the insulin tolerance test. In conclusion, we identified potent allosteric and pan-mutant selective PI3Kα inhibitors capable of degrading PI3Kα mutant protein. Our findings suggest that TYK compounds can significantly enhance the therapeutic index of PI3Kα-mutant cancers without causing PI3Kα WT-related toxicity. Citation Format: Chengshan Niu, Yusheng Wu. Identification and characterization of pan-mutant selective PI3Kα inhibitors with the capability of PI3Kα H1047R protein degradation abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5130.