title: Discovery of Disubstituted Imidazo[4,5-b]pyridines and Purines as Potent TrkA Inhibitors.
abstract: Trk receptor tyrosine kinases have been implicated in cancer and pain. A crystal structure of TrkA with AZ-23 (1a) was obtained, and scaffold hopping resulted in two 5/6-bicyclic series comprising either imidazo[4,5-b]pyridines or purines. Further optimization of these two fusion series led to compounds with subnanomolar potencies against TrkA kinase in cellular assays. Antitumor effects in a TrkA-driven mouse allograft model were demonstrated with compounds 2d and 3a.
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Lamb
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Block
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Audrey Molina
authors.initials: AM
authors.lastname: Davies
authors.affiliation: Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Yongxin
authors.initials: Y
authors.lastname: Han
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Ethan
authors.initials: E
authors.lastname: Hoffmann
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Stephanos
authors.initials: S
authors.lastname: Ioannidis
authors.affiliation: Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: John A
authors.initials: JA
authors.lastname: Josey
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Zhong-Ying
authors.initials: ZY
authors.lastname: Liu
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Lyne
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Terry
authors.initials: T
authors.lastname: MacIntyre
authors.affiliation: Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohr
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Omer
authors.affiliation: Discovery Sciences, Innovative Medicines, AstraZeneca , Pepparedsleden S431 83 Mölndal, Sweden.
authors.forename: Tove
authors.initials: T
authors.lastname: Sjögren
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Thress
authors.affiliation: Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Haiyun
authors.initials: H
authors.lastname: Wang
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Dingwei
authors.initials: D
authors.lastname: Yu
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Hai-Jun
authors.initials: HJ
authors.lastname: Zhang
keywords: Trk; cancer; imidazo[4,5-b]pyridines; kinase inhibitors; purines