RESEARCH ARTICLE


Phosphorylation State-Dependent High Throughput Screening of the c-Met Kinase



Elham Behshad*, Ronald M. Klabe, Alexander Margulis, Mary Becker-Pasha, Mark J. Rupar, Paul Collier, Phillip C. Liu, Gregory F. Hollis, Timothy C. Burn, Richard Wynn
Incyte Corporation, Applied Technology Group, Experimental Station, Route 141 & Henry Clay Road, Wilmington, DE 19880, USA


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© Behshad et al.; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

* Address correspondence to this author at the Incyte Corporation, Applied Technology Group, Experimental Station, Route 141 & Henry Clay Road, Wilmington, DE 19880, USA; Tel: (302) 498-6966; Fax: (302) 425-2721; E-mail: ebehshad@incyte.com


Abstract

High-throughput screening (HTS) of ~50,000 chemical compounds against phosphorylated and unphosphorylated c-Met, a tyrosine kinase receptor for hepatocyte growth factor (HGF), was carried out in order to compare hit rates, hit potencies and also to explore scaffolds that might serve as potential leads targeting only the unphosphorylated form of the enzyme. The hit rate and potency for the confirmed hit molecules were higher for the unphosphoryalted form of c-Met. While the target of small molecule inhibitor discovery efforts has traditionally been the phosphorylated form, there are now examples of small molecules that target unphosphorylated kinases. Screening for inhibitors of unphosphorylated kinases may represent a complementary approach for prioritizing chemical scaffolds for hit-to-lead follow ups.

Keywords: Kinase, phosphorylation, high throughput screening, HTRF, c-Met, cancer.