Quantitative structure‐selectivity relationship (QSSR)‐based molecular insight into the cross‐reactivity and specificity of chemotherapeutic inhibitors between PI3Kα and PI3Kβ

Abstract

Selective inhibition of phosphoinositide 3‐kinase (PI3K) isoforms α and β with small‐molecule inhibitors can result in distinct biological effects on anticancer chemotherapy. However, many existing PI3K inhibitors have moderate or high promiscuity and cross‐reactivity between the 2 kinase isoforms. Here, a quantitative structure‐selectivity relationship–based statistical modeling scheme was used to characterize the relative contribution of independent kinase residues to inhibitor selectivity and to predict the selectivity and specificity for existing PI3K inhibitors. It is found that the residue type and distribution of kinase's active site play an important role in inhibitor selectivity, while rest of the kinase may contribute to the selectivity through long‐range chemical interactions and indirect allosteric effect. The selectivity is also determined by the configuration difference between PI3Kα and PI3Kβ kinase domains. Larger inhibitor compounds have lower binding potency to PI3Kβ than PI3Kα and thus possess higher selectivity for PI3Kα over PI3Kβ.