Targeting PI3Kα with Small Molecules: Progress and Challenges in Tumor Treatment

Aberrant activation of PI3Kα tightly correlates with tumorigenesis and advancement. PI3Kα inhibitors can bring significant clinical gains to patients with PIK3CA-mutant breast cancer and other solid tumor patients by inhibiting tumor cell growth and regulating the immune microenvironment. Alpelisib, a selective PI3Kα inhibitor, has a more favorable benefit-to-risk ratio compared with earlier-generation pan-PI3K inhibitors, with more manageable risks of severe adverse events, including pneumonitis. CYH33 induces immune activation and synergizes with a FASN inhibitor to further promote antitumor immunity. In addition, inavolisib, which features a mutant-selective degradation mechanism, has already been approved for clinical use, while compounds with distinct mechanisms, such as the wild-type PI3Kα-sparing allosteric inhibitor STX-478, have demonstrated favorable preclinical results and are currently under phase I/II clinical research for PIK3CA-mutated advanced solid tumors. Apart from the above therapies, emerging drugs with differentiated mechanisms have shown great potential for clinical application in the years ahead. BEBT-908 not only inhibits the growth of tumor cells but also activates host anti-tumor immunity to strengthen immune checkpoint treatment. Additionally, ZM-PI05 represents a PROTAC agent that degrades the PI3Kα protein. Despite the evident clinical advantages of PI3Kα inhibitors, toxicities such as hyperglycemia, rash, and gastrointestinal reactions limit their popularization. Current research mainly focuses on designing selective PI3Kα inhibitors with improved safety and establishing optimal medication regimens. This paper discusses the biological roles of PI3Kα in tumors, summarizes clinical trials, common side effects, and binding characteristics of PI3Kα inhibitors, and proposes guidance for their further development and utilization.