Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 23, Issue 15, Pages 4398-4403Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2013.05.072
Keywords
Yes1; Kinase; Screening; HTS; Small molecule; Inhibitor; Rhabdomyosarcoma
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Funding
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences
- Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research
- National Human Genome Research Institute
- National Cancer Institute, Center for Cancer Research
- Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E, U54CA143930]
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Yes1 kinase has been implicated as a potential therapeutic target in a number of cancers including melanomas, breast cancers, and rhabdomyosarcomas. Described here is the development of a robust and miniaturized biochemical assay for Yes1 kinase that was applied in a high throughput screen (HTS) of kinase-focused small molecule libraries. The HTS provided 144 (17% hit rate) small molecule compounds with IC50 values in the sub-micromolar range. Three of the most potent Yes1 inhibitors were then examined in a cell-based assay for inhibition of cell survival in rhabdomyosarcoma cell lines. Homology models of Yes1 were generated in active and inactive conformations, and docking of inhibitors supports binding to the active conformation (DFG-in) of Yes1. This is the first report of a large high throughput enzymatic activity screen for identification of Yes1 kinase inhibitors, thereby elucidating the polypharmacology of a variety of small molecules and clinical candidates. (C) 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
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