title: Identification of novel series of pyrazole and indole-urea based DFG-out PYK2 inhibitors.
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.
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Global Research and Development, 620 Memorial Drive, Cambridge, MA 02139, United States. samit.k.bhattacharya@pfizer.com
authors.forename: Samit K
authors.initials: SK
authors.lastname: Bhattacharya
authors.forename: Gary E
authors.initials: GE
authors.lastname: Aspnes
authors.forename: Scott W
authors.initials: SW
authors.lastname: Bagley
authors.forename: Markus
authors.initials: M
authors.lastname: Boehm
authors.forename: Arthur D
authors.initials: AD
authors.lastname: Brosius
authors.forename: Leonard
authors.initials: L
authors.lastname: Buckbinder
authors.forename: Jeanne S
authors.initials: JS
authors.lastname: Chang
authors.forename: Joseph
authors.initials: J
authors.lastname: Dibrino
authors.forename: Heather
authors.initials: H
authors.lastname: Eng
authors.forename: Kosea S
authors.initials: KS
authors.lastname: Frederick
authors.forename: David A
authors.initials: DA
authors.lastname: Griffith
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Griffor
authors.forename: Cristiano R W
authors.initials: CR
authors.lastname: Guimarães
authors.forename: Angel
authors.initials: A
authors.lastname: Guzman-Perez
authors.forename: Seungil
authors.initials: S
authors.lastname: Han
authors.forename: Amit S
authors.initials: AS
authors.lastname: Kalgutkar
authors.forename: Jacquelyn
authors.initials: J
authors.lastname: Klug-McLeod
authors.forename: Carmen
authors.initials: C
authors.lastname: Garcia-Irizarry
authors.forename: Jianke
authors.initials: J
authors.lastname: Li
authors.forename: Blaise
authors.initials: B
authors.lastname: Lippa
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: James A
authors.initials: JA
authors.lastname: Southers
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Walker
authors.forename: Liuqing
authors.initials: L
authors.lastname: Wei
authors.forename: Jun
authors.initials: J
authors.lastname: Xiao
authors.forename: Michael P
authors.initials: MP
authors.lastname: Zawistoski
authors.forename: Xumiao
authors.initials: X
authors.lastname: Zhao
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D051418:Focal Adhesion Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D014508:Urea; D051418:Focal Adhesion Kinase 2