Discovery of a Highly Selective JAK2 Inhibitor, BMS-911543, for the Treatment of Myeloproliferative Neoplasms
- Honghe Wan
- ,
- Gretchen M. Schroeder
- ,
- Amy C. Hart
- ,
- Jennifer Inghrim
- ,
- James Grebinski
- ,
- John S. Tokarski
- ,
- Matthew V. Lorenzi
- ,
- Dan You
- ,
- Theresa Mcdevitt
- ,
- Becky Penhallow
- ,
- Ragini Vuppugalla
- ,
- Yueping Zhang
- ,
- Xiaomei Gu
- ,
- Ramaswamy Iyer
- ,
- Louis J. Lombardo
- ,
- George L. Trainor
- ,
- Stefan Ruepp
- ,
- Jonathan Lippy
- ,
- Yuval Blat
- ,
- John S. Sack
- ,
- Javed A. Khan
- ,
- Kevin Stefanski
- ,
- Bogdan Sleczka
- ,
- Arvind Mathur
- ,
- Jung-Hui Sun
- ,
- Michael K. Wong
- ,
- Dauh-Rurng Wu
- ,
- Peng Li
- ,
- Anuradha Gupta
- ,
- P. N. Arunachalam
- ,
- Bala Pragalathan
- ,
- Sankara Narayanan
- ,
- Nanjundaswamy K.C.
- ,
- Prakasam Kuppusamy
- , and
- Ashok V. Purandare
Abstract

JAK2 kinase inhibitors are a promising new class of agents for the treatment of myeloproliferative neoplasms and have potential for the treatment of other diseases possessing a deregulated JAK2-STAT pathway. X-ray structure and ADME guided refinement of C-4 heterocycles to address metabolic liability present in dialkylthiazole 1 led to the discovery of a clinical candidate, BMS-911543 (11), with excellent kinome selectivity, in vivo PD activity, and safety profile.
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