Docking to erlotinib off-targets leads to inhibitors of lung cancer cell proliferation with suitable in vitro pharmacokinetics

In an effort to develop a rational approach to identify anticancer agents with selective polypharmacology, we mined millions of docked protein?ligand complexes involving more than a thousand cancer targets from multiple signaling pathways to identify new structural templates for proven pharmacophores. Our method combines support vector machine-based scoring to enrich the initial library of 1592 molecules, with a fingerprint-based search for molecules that have the same binding profile as the EGFR kinase inhibitor erlotinib. Twelve new compounds were identified. In vitro activity assays revealed three inhibited EGFR with IC₅₀ values ranging from 250 nM to 200 ?M. Additional in vitro studies with hERG, CYP450, DNA, and cell culture-based assays further compared their properties to erlotinib. One compound combined suitable pharmacokinetic properties while closely mimicking the binding profile of erlotinib. The compound also inhibited H1299 and H460 tumor cell proliferation. The other two compounds shared some of the binding profile of erlotinib, and one gave the most potent inhibition of tumor cell growth. Interestingly, among the compounds that had not shown inhibition of EGFR, four blocked H1299 and H460 proliferation, one potently with IC₅₀ values near 1 ?M. This compound was from the menogaril family, which reached phase II clinical trials for the treatment of lymphomas. This suggests that our computational approach comparing binding profiles may have favored molecules with anticancer properties like erlotinib.