Synthesis of aryl-heteroaryl ureas (AHUs) based on 4-aminoquinoline and their evaluation against the insulin-like growth factor receptor (IGF-1R) |
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Authors: | William Engen Terrence E O’Brien Brendan Kelly Jacinda Do Liezel Rillera Lance K Stapleton Jack F Youngren Marc O Anderson |
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Affiliation: | 1. Department of Chemistry & Biochemistry, San Francisco State University, 1600 Holloway Ave., San Francisco, CA 94132, USA;2. Diabetes and Endocrine Research, University of California, San Francisco/Mt. Zion Medical Center, Box 1616, San Francisco, CA 94143-1616, USA |
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Abstract: | The insulin-like growth factor receptor (IGF-1R) is a receptor tyrosine kinase (RTK) involved in all stages of the development and propagation of breast and other cancers. The inhibition of IGF-1R by small molecules remains a promising strategy to treat cancer. Herein, we explore SAR around previously characterized lead compound (1), which is an aryl-heteroaryl urea (AHU) consisting of 4-aminoquinaldine and a substituted aromatic ring system. A library of novel AHU compounds was prepared based on derivatives of the 4-aminoquinoline heterocycle (including various 2-substituted derivatives, and naphthyridines). The compounds were screened for in vitro inhibitory activity against IGF-1R, and several compounds with improved activity (3–5 μM) were identified. Furthermore, a computational docking study was performed, which identifies a fairly consistent lowest energy mode of binding for the more-active set of inhibitors in this series, while the less-active inhibitors do not adopt a consistent mode of binding. |
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