Current Chemical Genomics and Translational Medicine

2010, 4 : 27-33
Published online 2010 April 23. DOI: 10.2174/1875397301004010027
Publisher ID: CCGTM-4-27

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 and Richard Wynn
Incyte Corporation, Applied Technology Group, Experimental Station, Route 141 & Henry Clay Road, Wilmington, DE 19880, USA

* 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.