Synthesis of aryl-heteroaryl ureas (AHUs) based on 4-aminoquinoline and their evaluation against the insulin-like growth factor receptor (IGF-1R).

Bioorganic & Medicinal Chemistry
William EngenM O Anderson

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 microM) 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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Citations

May 8, 2014·Chemical Biology & Drug Design·Núbia BoechatAntoniana U Krettli
May 12, 2015·European Journal of Pharmacology·Vandana Srivastava, Hoyun Lee
Mar 6, 2015·Bioorganic & Medicinal Chemistry·Scott J BarrazaScott D Larsen
Mar 25, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jakob HalekotteChristian Peifer
Jan 22, 2013·Artificial Cells, Nanomedicine, and Biotechnology·Nahit GençerMustafa Küçükislamoğlu

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