title: Discovery of 7-azaindole based anaplastic lymphoma kinase (ALK) inhibitors: wild type and mutant (L1196M) active compounds with unique binding mode.
abstract: We have identified a novel 7-azaindole series of anaplastic lymphoma kinase (ALK) inhibitors. Compounds 7b, 7 m and 7 n demonstrate excellent potencies in biochemical and cellular assays. X-ray crystal structure of one of the compounds (7 k) revealed a unique binding mode with the benzyl group occupying the back pocket, explaining its potency towards ALK and selectivity over tested kinases particularly Aurora-A. This binding mode is in contrast to that of known ALK inhibitors such as Crizotinib and NVP-TAE684 which occupy the ribose binding pocket, close to DFG motif.
authors.affiliation: Aurigene Discovery Technologies Ltd, #39/40, KIADB Industrial Area, Hosur Road, Electronic City Phase-II, Bangalore 560100, India.
authors.forename: Venkateshwar Rao
authors.initials: VR
authors.lastname: Gummadi
authors.forename: Sujatha
authors.initials: S
authors.lastname: Rajagopalan
authors.forename: Chung-Yeng
authors.initials: CY
authors.lastname: Looi
authors.forename: Mohammadjavad
authors.initials: M
authors.lastname: Paydar
authors.forename: Girish Aggunda
authors.initials: GA
authors.lastname: Renukappa
authors.forename: Bharathi Raja
authors.initials: BR
authors.lastname: Ainan
authors.forename: Narasimha Rao
authors.initials: NR
authors.lastname: Krishnamurthy
authors.forename: Sunil Kumar
authors.initials: SK
authors.lastname: Panigrahi
authors.forename: Kumari
authors.initials: K
authors.lastname: Mahasweta
authors.forename: Sangeetha
authors.initials: S
authors.lastname: Raghuramachandran
authors.forename: Manoj
authors.initials: M
authors.lastname: Rajappa
authors.forename: Anuradha
authors.initials: A
authors.lastname: Ramanathan
authors.forename: Anirudha
authors.initials: A
authors.lastname: Lakshminarasimhan
authors.forename: Murali
authors.initials: M
authors.lastname: Ramachandra
authors.forename: Pooi-Fong
authors.initials: PF
authors.lastname: Wong
authors.forename: Mohammad Rais
authors.initials: MR
authors.lastname: Mustafa
authors.forename: Srinivas
authors.initials: S
authors.lastname: Nanduri
authors.forename: Subramanya
authors.initials: S
authors.lastname: Hosahalli
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: C023422:7-azaindole dimer; D007211:Indoles; D047428:Protein Kinase Inhibitors; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: 7-Azaindole; AODVBYYJEPEEKR-UHFFFAOYSA-N; ATZJNUYRMAFPBF-UHFFFAOYSA-N; Anaplastic large cell lymphoma (ALCL); Anaplastic lymphoma kinase (ALK); Cancer; FADONZKXBUVWLH-UHFFFAOYSA-N; FPQUAATUWBOAGG-UHFFFAOYSA-N; HCWGKZMWRCORGX-UHFFFAOYSA-N; ISOJIFQFHFOCFC-UHFFFAOYSA-N; JJYRLIVLBDHFEU-UHFFFAOYSA-N; KNRKBZCJMLVHPB-UHFFFAOYSA-N; Karpas299; LKQKEJPUPWXICV-UHFFFAOYSA-N; LRWNZUVVRSBHQU-UHFFFAOYSA-N; MGARIFYNPCFMQT-UHFFFAOYSA-N; NAKSXXPCEJGLLQ-UHFFFAOYSA-N; PGSYBTKGCJXUAV-UHFFFAOYSA-N; SDWMCZUOCJDBOJ-UHFFFAOYSA-N; WIWKHKMJZYIJLG-UHFFFAOYSA-N; WXMICXPDNXUCTC-UHFFFAOYSA-N; XUQBNEPFDRSOCA-UHFFFAOYSA-N; ZHUGMFFQPPOJNL-UHFFFAOYSA-N