title: Navigating into the binding pockets of the HER family protein kinases: discovery of novel EGFR inhibitor as antitumor agent.
abstract: The epidermal growth factor receptor (EGFR) family has been validated as a successful antitumor drug target for decades. Known EGFR inhibitors were exposed to distinct drug resistance against the various EGFR mutants within non-small-cell lung cancer (NSCLC), particularly the T790M mutation. Although so far a number of studies have been reported on the development of third-generation EGFR inhibitors for overcoming the resistance issue, the design procedure largely depends on the intuition of medicinal chemists. Here we retrospectively make a detailed analysis of the 42 EGFR family protein crystal complexes deposited in the Protein Data Bank (PDB). Based on the analysis of inhibitor binding modes in the kinase catalytic cleft, we identified a potent EGFR inhibitor (compound A-10) against drug-resistant EGFR through fragment-based drug design. This compound showed at least 30-fold more potency against EGFR T790M than the two control molecules erlotinib and gefitinib in vitro. Moreover, it could exhibit potent HER2 inhibitory activities as well as tumor growth inhibitory activity. Molecular docking studies revealed a structural basis for the increased potency and mutant selectivity of this compound. Compound A-10 may be selected as a promising candidate in further preclinical studies. In addition, our findings could provide a powerful strategy to identify novel selective kinase inhibitors on the basis of detailed kinase-ligand interaction space in the PDB.
authors.affiliation: The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: The Thoracic Surgery Department, Harbin Medical University Cancer Hospital, Harbin, People's Republic of China.
authors.forename: Jin-Feng
authors.initials: JF
authors.lastname: Ning
authors.affiliation: The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People's Republic of China.
authors.forename: Qing-Wei
authors.initials: QW
authors.lastname: Meng
authors.affiliation: The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Hu
authors.affiliation: The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People's Republic of China.
authors.forename: Yan-Bin
authors.initials: YB
authors.lastname: Zhao
authors.affiliation: General Surgery Department, Mudanjiang Guanliju Central Hospital, Mishan, Heilongjiang Province, People's Republic of China.
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
authors.affiliation: The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Cai
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015195:Drug Design; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology; D000077156:Gefitinib; D006801:Humans; D062105:Molecular Docking Simulation; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D012189:Retrospective Studies
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
keywords: EGFR; FBDD; erlotinib; inhibitor; kinase; protein crystal complex