Discovery of a selective PI3Kα inhibitor via structure-based virtual screening for targeted colorectal cancer therapy

Colorectal Cancer (CRC) remains a leading cause of cancer-related mortality globally, driving an urgent need for effective therapies. A promising avenue of research focuses on the PI3K/Akt/mTOR signalling pathway, which is frequently disrupted by mutations in the PI3Kα subunit. Our cutting-edge study employed a structure-based virtual screening of ∼3000 compounds, leading to the discovery of F0608-0019, a highly potent and selective PI3Kα Inhibitor. F0608-0019 demonstrated remarkable efficacy in suppressing HCT116 colorectal Cancer cell proliferation, with an IC₅₀ of 12.14 µM, while maintaining high selectivity by minimising activity against Other PI3K isoforms. Advanced molecular dynamics simulations highlighted the stability of F0608-0019's binding interactions with key Amino acids, such as TRP:780, ILE:932, and VAL:850, which are critical for its targeted action. These exciting findings reveal F0608-0019 as a leading candidate for innovative CRC therapies that selectively target PI3Kα dysregulation, offering promising new possibilities for effective CRC treatment.

Colorectal cancer; PI3K signalling pathway; PI3Kα inhibitor; cancer drug discovery; structure-based virtual screening.