2. Academic Validation
  3. Identification of novel series of pyrazole and indole-urea based DFG-out PYK2 inhibitors

Identification of novel series of pyrazole and indole-urea based DFG-out PYK2 inhibitors

  • Bioorg Med Chem Lett. 2012 Dec 15;22(24):7523-9. doi: 10.1016/j.bmcl.2012.10.039.
Samit K Bhattacharya 1,  Gary E Aspnes,  Scott W Bagley,  Markus Boehm,  Arthur D Brosius,  Leonard Buckbinder,  Jeanne S Chang,  Joseph Dibrino,  Heather Eng,  Kosea S Frederick,  David A Griffith,  Matthew C Griffor,  Cristiano R W Guimarães,  Angel Guzman-Perez,  Seungil Han,  Amit S Kalgutkar,  Jacquelyn Klug-McLeod,  Carmen Garcia-Irizarry,  Jianke Li,  Blaise Lippa,  David A Price,  James A Southers,  Daniel P Walker,  Liuqing Wei,  Jun Xiao,  Michael P Zawistoski,  Xumiao Zhao
Affiliations

Affiliation

  • 1 Worldwide Medicinal Chemistry, Pfizer Global Research and Development, 620 Memorial Drive, Cambridge, MA 02139, United States. samit.k.bhattacharya@pfizer.com
PMID: 23153798 DOI: 10.1016/j.bmcl.2012.10.039
Abstract

Previous drug discovery efforts identified classical Pyk2 kinase inhibitors such as 2 and 3 that possess selectivity for Pyk2 over its intra-family isoform FAK. Efforts to identify more kinome-selective chemical matter that stabilize a DFG-out conformation of the Enzyme are described herein. Two sub-series of Pyk2 inhibitors, an indole carboxamide-urea and a pyrazole-urea have been identified and found to have different binding interactions with the hinge region of Pyk2. These leads proved to be more selective than the original classical inhibitors.

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