title: Integrated Exploitation of the Structural Diversity Space of Chemotherapy Drugs to Selectively Inhibit HER2 T798M Mutant in Lung Cancer.
abstract: An acquired T798M gatekeeper mutation in human epidermal growth factor receptor 2 (HER2) kinase can cause drug resistance to anti-HER2 chemotherapy drugs in lung cancer. Previously, the reversible pan-kinase inhibitor staurosporine has been found to selectively inhibit the HER2 T798M mutant over wild-type kinase, suggesting that the staurosporine scaffold is potentially to develop mutant-selective inhibitors. Here, we systematically evaluated the chemical space of staurosporine scaffold-based compounds in response to HER2 T798M mutation at structural, energetic and molecular levels by using an integrated analysis strategy. With this strategy, we were able to identify several novel wild-type sparing inhibitors with high or moderate selectivity, which are comparable to or even better than that of the parent compound staurosporine. Molecular modeling and structural analysis revealed that noncovalent contacts can form between the side chain of mutated residue Met798 and selective inhibitor ligands, which may improve the favorable interaction energy between the kinase and inhibitor and reduce the unfavorable desolvation penalty upon the kinase-inhibitor binding.
authors.affiliation: Department of Chemotherapy, Cancer Center, Qilu Hospital, Shandong University, Jinan, 250012, P. R. China.
authors.forename: Ya-Wei
authors.initials: YW
authors.lastname: Wang
authors.affiliation: Department of Otorhinolaryngology Head and Neck Surgery, Provincial Hospital affiliated to Shandong University, Jinan, 250021, P. R. China.
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Zhang
authors.affiliation: Department of Chemotherapy, Cancer Center, Qilu Hospital, Shandong University, Jinan, 250012, P. R. China.
authors.forename: Ji-Sheng
authors.initials: JS
authors.lastname: Li
authors.affiliation: Department of Chemotherapy, Cancer Center, Qilu Hospital, Shandong University, Jinan, 250012, P. R. China.
authors.forename: Xiu-Wen
authors.initials: XW
authors.lastname: Wang
mesh_terms: D001665:Binding Sites; D002227:Carbazoles / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D005663:Furans; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D062105:Molecular Docking Simulation; D009154:Mutation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019311:Staurosporine / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D002227:Carbazoles; D005663:Furans; D008024:Ligands; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D019311:Staurosporine; C119379:lestaurtinib; C508053:ERBB2 protein, human
keywords: Chemical space; Chemotherapy drug; Human epidermal growth factor receptor 2; Lung cancer; Structural diversity; T798M Gatekeeper mutation