title: Identification of novel anaplastic lymphoma kinase (ALK) inhibitors using a common feature pharmacophore model derived from known ligands crystallized with ALK.
abstract: In this investigation, a common feature pharmacophore model of anaplastic lymphoma kinase inhibitors was developed based on several known anaplastic lymphoma kinase inhibitors that were co-crystallized with anaplastic lymphoma kinase. The established pharmacophore model Hypo1 was carefully validated and then adopted to screen two in silico chemical databases, Specs (202 408 compounds) and Enamine (1 105 894 compounds), for retrieving novel anaplastic lymphoma kinase inhibitors. The hit compounds were further filtered using a fast bumping-check tool and molecular docking. Finally, 25 compounds were selected and purchased from market. The bioactivity of these compounds was firstly measured at the cellular level against a typical anaplastic lymphoma kinase mutant-driven cancer cell line, Karpas299. And six of them showed a good anti-viability activity. The kinase inhibitory potency against the recombinant human anaplastic lymphoma kinase kinase was tested to the most active compound at the cellular level, T0508-5181 (from Specs), which gave a half maximal inhibitory concentration (IC(50)) of 5.3 μM.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan 610041, China.
authors.forename: Huan-Zhang
authors.initials: HZ
authors.lastname: Xie
authors.forename: Hai
authors.initials: H
authors.lastname: Lan
authors.forename: You-Li
authors.initials: YL
authors.lastname: Pan
authors.forename: Jun
authors.initials: J
authors.lastname: Zou
authors.forename: Ze-Rong
authors.initials: ZR
authors.lastname: Wang
authors.forename: Lin-Li
authors.initials: LL
authors.lastname: Li
authors.forename: Qi
authors.initials: Q
authors.lastname: Huang
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Sheng-Yong
authors.initials: SY
authors.lastname: Yang
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D047428:Protein Kinase Inhibitors; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases