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Published on: June 23, 2019
Discovery of Disubstituted Imidazo[4,5-b]pyridines and Purines as Potent TrkA Inhibitors
Tao Wang1, Michelle L Lamb1, Michael H Block1
1Oncology Innovative Medicines Unit, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
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.
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