The phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway plays a critical role in the regulation of cellular growth, survival and proliferation. mTOR and PI3K have attracted particular attention as cancer targets. These kinases belong to the phosphatidylinositol-3-kinase-related kinase (PIKK) family and therefore have considerable homology in their active sites. To accelerate the discovery of inhibitors with selective activity against mTOR and PI3K as cancer targets, in this work, a homology model of mTOR was developed to identify the structural divergence in the active sites between mTOR and PI3Kα. Furthermore, two highly predictive comparative molecular similarity index analyses (CoMSIA) models were built based on 304 selective inhibitors docked into mTOR and PI3Kα, respectively (mTOR: q(2) = 0.658, r(pre)(2) = 0.839; PI3Kα: q(2) = 0.540, r(pre)(2) = 0.719). The results showed that steric and electrostatic fields have an important influence on selectivity towards mTOR and PI3Kα-a finding consistent with the structural divergence between the active sites. The findings may be helpful in investigating selective mTOR/PI3Kα inhibitors.