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.
References
Oct 8, 1993·Cell·J BakerA Efstratiadis
Jun 28, 2001·Oncogene·M J Morin
Sep 23, 2003·Acta Crystallographica. Section D, Biological Crystallography·Sanjeev MunshiLawrence C Kuo
Nov 6, 2003·International Journal of Cancer. Journal International Du Cancer·Renato BasergaKrysztof Reiss
Jan 10, 2004·Integrative Cancer Therapies·D Barry Boyd
Mar 31, 2004·Cancer Cell·Derek LeRoith, Lee Helman
Mar 31, 2004·Cancer Cell·Carlos García-EcheverríaFrancesco Hofmann
Aug 2, 2005·Drug Discovery Today·Francesco Hofmann, Carlos García-Echeverría
May 2, 2006·Molecular Cancer Therapeutics·Karissa L GableJack F Youngren
Apr 16, 2008·Expert Opinion on Therapeutic Targets·John S P Yuen, Valentine M Macaulay
Sep 16, 2008·Molecular Cancer Therapeutics·Jordi RodonRazelle Kurzrock
Nov 22, 2008·Journal of Mammary Gland Biology and Neoplasia·S John Weroha, Paul Haluska
Jan 20, 2009·Recent Patents on Anti-cancer Drug Discovery·Madeleine HewishDavid Cunningham
Jul 28, 2009·Clinical Lung Cancer·Antonio Gualberto, Daniel D Karp
Aug 12, 2009·Expert Opinion on Therapeutic Targets·Ilan BruchimHaim Werner
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