Rational creation and systematic analysis of cervical cancer kinase-inhibitor binding profile.

Abstract

The kinase-regulatory cell signaling networks play a central role in the pathogenesis of human cervical cancer (hCC). However, only few kinase inhibitors have been successfully developed for treatment of this cancer to date. Considering that the active sites of protein kinases are highly conserved and small-molecule inhibitors should generally exhibit high promiscuity and broad specificity across the hCC-related kinase array, it is supposed that the established kinase targets of hCC can be targeted unexpectedly by certain noncognate kinase inhibitors. This provides a novel idea to practice the new uses for old drugs in anti-cancer chemotherapy. Here, we create a systematic kinase-inhibitor binding profile in a high-throughput manner by molecular docking and consensus scoring, where the kinases have been collected as therapeutic targets of hCC and the inhibitors are reversible, ATP-competitive and readily available. The docking/scoring scheme is tested rigorously with structure-solved and affinity-known kinase-inhibitor complex samples, which is later demonstrated to be effective in inferring unexpected inhibitor response to hCC-related kinases. Few promising kinase-inhibitor pairs are identified from the profile and tested experimentally at cellular and molecular levels. It is found that the kinase-inhibitor promiscuity is a common phenomenon but only few can interaction effectively and inhibit potently. In addition, the high-scoring inhibitors generally exhibit good suppressing potency on hCC cell viability as compared to those low-scoring ones, imparting that the created profile can well reflect the tumor cytotoxicity of noncognate kinase inhibitors. A further kinase assay suggests that the ErbB family kinases are the potential targets of these high-scoring inhibitors, with noncognate inhibitory activity up to nanomolar level. Structure analysis reveals that the nonbonded interactions of potent noncogante kinase-inhibitor binding can divided into a polar tail and a nonpolar lobe, which confer specificity and stability to the binding, respectively.