2. Academic Validation
  3. Discovery of Disubstituted Imidazo[4,5-b]pyridines and Purines as Potent TrkA Inhibitors

Discovery of Disubstituted Imidazo[4,5-b]pyridines and Purines as Potent TrkA Inhibitors

  • ACS Med Chem Lett. 2012 Jul 26;3(9):705-9. doi: 10.1021/ml300074j.
Tao Wang 1,  Michelle L Lamb 1,  Michael H Block 1,  Audrey Molina Davies 1,  Yongxin Han 2,  Ethan Hoffmann 1,  Stephanos Ioannidis 1,  John A Josey 2,  Zhong-Ying Liu 1,  Paul D Lyne 1,  Terry MacIntyre 1,  Peter J Mohr 2,  Charles A Omer 1,  Tove Sjögren 3,  Kenneth Thress 1,  Bin Wang 2,  Haiyun Wang 1,  Dingwei Yu 1,  Hai-Jun Zhang 1
Affiliations

Affiliations

  • 1 Oncology Innovative Medicines Unit, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
  • 2 Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States.
  • 3 Discovery Sciences, Innovative Medicines, AstraZeneca , Pepparedsleden S431 83 Mölndal, Sweden.
PMID: 24900538 DOI: 10.1021/ml300074j
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.

Keywords

Trk; cancer; imidazo[4,5-b]pyridines; kinase inhibitors; purines.

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