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

• Published in: Bioorganic & medicinal chemistry letters Vol. 22; no. 24; pp. 7523 - 7529
• Main Authors: Bhattacharya, Samit K., Aspnes, Gary E., Bagley, Scott W., Boehm, Markus, Brosius, Arthur D., Buckbinder, Leonard, Chang, Jeanne S., Dibrino, Joseph, Eng, Heather, Frederick, Kosea S., Griffith, David A., Griffor, Matthew C., Guimarães, Cristiano R.W., Guzman-Perez, Angel, Han, Seungil, Kalgutkar, Amit S., Klug-McLeod, Jacquelyn, Garcia-Irizarry, Carmen, Li, Jianke, Lippa, Blaise, Price, David A., Southers, James A., Walker, Daniel P., Wei, Liuqing, Xiao, Jun, Zawistoski, Michael P., Zhao, Xumiao
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15-12-2012; Elsevier
• Subjects: Animals; Biological and medical sciences; BIRB-796; chemistry; Conformation; Crystallography, X-Ray; DFG-out; Dose-Response Relationship, Drug; Drug discovery; drugs; enzyme inhibitors; Enzymes; FAK; Focal adhesion kinase; Focal Adhesion Kinase 2 - antagonists & inhibitors; Focal Adhesion Kinase 2 - metabolism; HEK293 Cells; Humans; Indole; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Kinase inhibitor; Medical sciences; Models, Molecular; Molecular Structure; non-specific protein-tyrosine kinase; Osteoporosis; Pharmacology. Drug treatments; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; PYK2; pyrazoles; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Rats; Structure-Activity Relationship; Urea - analogs & derivatives; Urea - chemistry; Urea - pharmacology; FAK; Osteoporosis; PYK2; Kinase inhibitor; BIRB-796; DFG-out; Enzyme; Transferases; Diseases of the osteoarticular system; Non-specific protein-tyrosine kinase; Pyrazole; Doramapimod; Immunomodulator; Signal transduction; Urea; Kinase; Pyrazole derivatives; Ureas; Inhibitor; Indole derivatives
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.10.039

Two highly selective sub–series of DFG-out leads for PYK2, an indole-urea and a pyrazole-urea were identified, and found to bind with different interactions in the hinge region of PYK2.
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.