Phosphatidylinositol 3-kinase α is an attractive target to potentially treat a range of cancers. Herein, we described the evolution of a reported PI3K inhibitor into a moderate PI3Kα inhibitor with a low molecular weight. We used X-ray crystallography to describe the accurate binding mode of the compound YXY-4F. A comparison of the p110α–YXY-4F and apo p110α complexes showed that YXY-4F induced additional space by promoting a fexible conformational change in residues Ser773 and Ser774 in the PI3Kα ATP catalytic site. Specifcally, residue 773(S) in PI3Kα is quite diferent from that of PI3Kβ (D), γ (A), and δ (D), which might guide further optimization of substituents around the NH group and phenyl group to improve the selectivity and potency of PI3Kα.
Yang, X., Zhang, X., Huang, M., Song, K., Li, X., Huang, M., Meng, L., & Zhang, J. (2017). New Insights into PI3K Inhibitor Design using X-ray Structures of PI3Kα Complexed with a Potent Lead Compound. Scientific Reports, 7, 1-7. . https://doi.org/10.1038/s41598-017-15260-5