Abstract 3002: GSC002639, a brain penetrating and mutant-selective PI3Kα inhibitor, exhibits potent mono- and combination therapy against PI3CA mutant tumors
Authors: Xing Fan, Sheng Zhao, Hang Xu, Biao Lu, Yuanfeng Xia, Fanglong Yang
Journal: Cancer Research (2025)

Abstract Background: PIK3CA gene mutation is recognized as a significant driver of oncogenesis in various human cancers. Approximately 30% of breast cancers, 25% of endometrial cancers, 15% of colorectal cancers, 10% of ovarian cancers, and 5% of lung cancers exhibit mutations in the PIK3CA gene. The approvals of Alpelisib and Inavolisib have demonstrated the therapeutic benefits of PI3Kα inhibition for patients with PIK3CA mutations. However, their inhibition of wild-type PI3Kα leads to side effects such as hyperglycemia with insulin resistance, rash, and diarrhea, which limit their efficacy. Material and Methods: The suppressive effects on cell proliferation and phosphorylated AKT were analyzed across cellular models harboring various PIK3CA mutations. The capacity of GSC002639 to inhibit the isoforms PI3Kβ, PI3Kγ, and PI3Kδ, along with additional kinases, was determined through in vitro kinase activity tests. CDX model were used for in vivo efficacy evaluation. Furthermore, the pharmacodynamic properties of GSC002639 and its impact on glucose imbalance were investigated following established procedures. Preclinical toxicology studies were conducted with GSC002639 over 28 days of dosing in rats and dogs. Results: GSC002639 exhibited nanomolar potency against PI3Kα hotspot mutations while maintaining approximately 30-fold selectivity over the wild-type PI3Kα. Furthermore, GSC002639 displayed excellent selectivity over other PI3K isoforms, including PI3Kβ, δ, and γ. GSC002639 showed favorable pharmacokinetic properties and strong antitumor activity against cancer cells that express the PI3Kα H1047X mutations, without causing elevated plasma insulin levels, even at high dosages. Our study also revealed a notable observation: In an HR-positive and HER2-negative PI3Kα H1047X CDX model, the combination of GSC002639 with Fulvestrant exhibited greater efficacy than the combinations of either Alpelisib or Inavolisib with Fulvestrant. In addition, GSC002639 showed good brain penetrating capability with a brain/plasma ratio of 0.26. In preclinical toxicology studies, GSC002639 demonstrated excellent therapeutic safety window in F/M rats with 14.6/12.7 folds and in F/M dogs with15.3/28.1 folds, respectively. Conclusions: In this report, we present the identification and characterization of GSC002639, a selective inhibitor targeting the PI3Kα H1047X mutation. GSC002639 demonstrates high specificity, the ability to cross the blood-brain barrier, and robust in vivo efficacy, while avoiding the insulin elevation. The promising pharmacokinetic and toxicological profiles of GSC002639 suggest its potential as a safe and effective cancer therapy. GSC002639 is undergoing IND-enabling studies, with plans for its clinical evaluation as both a single-agent therapy and in combination regimens for patients with PI3Kα mutant cancers by early 2025. Citation Format: Xing Fan, Sheng Zhao, Hang Xu, Biao Lu, Yuanfeng Xia, Fanglong Yang. GSC002639, a brain penetrating and mutant-selective PI3Kα inhibitor, exhibits potent mono- and combination therapy against PI3CA mutant 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 3002.