Trk receptor tyrosine kinases have been implicated in cancer and pain. A crystal structure of TrkA with A
Z-23 (
1a) was obtained, and scaffold hopping resulted in two 5/6-bicyclic series comprising either imida
zo[4,5-
b]pyridines or purines. Further optimi
zation 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.
Keywords:
Trk; kinase inhibitors; zo%5C%5B4%2C5%5C-b%5C%5Dpyridines&qsSearchArea=searchText">imidazo[4,5-b]pyridines; purines; cancer