GenSci145：一种克服脑转移治疗障碍的突变选择性PI3Kalpha抑制剂

Background: PIK3CA gene mutations are important targets in cancer treatment and are widely present in various solid tumors. Existing PI3Kalpha inhibitors lack sufficient selectivity for mutant subtypes, which can lead to dose-limiting toxicities such as abnormal glucose metabolism and skin toxicity, affecting patient tolerance and long-term efficacy. Moreover, PIK3CA mutations may increase the risk of central nervous system (CNS) metastasis in patients. Existing inhibitors have extremely poor permeability across the blood-brain barrier, making it difficult to effectively suppress brain metastases and allowing the CNS to become a “sanctuary” for tumor recurrence. Therefore, the development of highly selective PI3Kalpha mutation inhibitors with brain-penetrating capabilities has become a key research direction to improve the prognosis of such patients. Methods: The activity of GenSci145 against PI3Kalpha mutant/wild-type cells was evaluated through in vitro experiments (CTG proliferation inhibition, HTRF detection of pAKT, kinase selectivity panel). In vivo experiments used CDX (T47D, CAL-33, GP2D), PDX (BR9466, etc.), and brain metastasis models (intracranial + subcutaneous transplantation) to analyze the anti-tumor effects of monotherapy or in combination with fulvestrant (TGI, CFB (change from baseline)). Results: In in-vi tro experiments, GenSci145 exhibited nanomolar-level inhibitory activity against PI3Kalpha mutants (H1047R, E545K, E542K) (IC 50 : 20-162 nM). It significantly inhibited proliferation (T47D IC 50 : 120.6 nM, selectivity 28.6-fold) and pAKT signaling (IC 50 : 67.5 nM, selectivity 11.3-fold) in mutant cells, with no significant effects on other PI3K subtypes or off-target kinases.In in-vivo experiments, GenSci145 showed dose-dependent anti-tumor effects in HR-positive, HER2-negative breast cancer CDX/PDX models, with significant synergy when combined with fulvestrant. In the xxT47D-Luc brain metastasis + subcutaneous model, GenSci145 dose-dependently inhibited both subcutaneous and intracranial tumors. For intracranial tumors, the CFB was 4.78 at 25 mg/kg and 1.71 at 100 mg/kg, which was superior to STX-478 (100 mg/kg, CFB=9.56). The results indicated that GenSci145 has the potential to treat patients with brain metastases. Conclusion: GenSci145 is a highly selective PI3Kalpha mutant inhibitor that mechanistically avoids the metabolic side effects of traditional inhibitors. Preclinical studies have shown significant anti-tumor effects in various PIK3CA mutant tumor models, with excellent blood-brain barrier penetration and effective inhibition of brain metastases. Overall, GenSci145 is expected to overcome the clinical limitations of existing PI3Kalpha inhibitors and provide a new treatment option for patients with PIK3CA mutations. It is currently being advanced to the IND application stage.