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Molecules 2013, 18(6), 6491-6503; doi:10.3390/molecules18066491
Article

The Design and Synthesis of a New Class of RTK/HDAC Dual-Targeted Inhibitors

1
, 2
, 3
, 3
 and 1,*
1 Institute of Drug Discovery and Development, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China 2 School of Life Sciences, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China 3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, SIBS, Chinese Academy of Sciences, Shanghai 201203, China
* Author to whom correspondence should be addressed.
Received: 13 May 2013 / Revised: 21 May 2013 / Accepted: 24 May 2013 / Published: 3 June 2013
(This article belongs to the Section Medicinal Chemistry)
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Abstract

Over the years, the development of targeted medicines has made significant achievements. As a typical example, receptor tyrosine kinases (RTK) inhibitors have become important chemotherapy drugs for a variety of cancers. However, the effectiveness of these agents is always hindered by poor response rates and acquired drug resistance. In order to overcome these limitations, several dual-targeted inhibitors with quinazoline core were designed and synthesized. Though these compounds can simultaneously inhibit histone deacetylases (HDAC) as well as RTK, the structure-activity relationship (SAR) is still not clear enough. To further explore this type of dual-targeted inhibitors, a new class of quinazoline derivatives were designed and synthesized. Their activity evaluations include in vitro inhibitory activity of HDAC, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). The SAR study indicated that the introduction of polar group such as hydroxamate on the 4-position of the quinazoline core is more likely to provide a potent HDACi/HER2i hybrid rather than HDACi/EGFRi molecule.
Keywords: receptor tyrosine kinases; histone deacetylase; antitumor; synergistic effect; dual inhibitor receptor tyrosine kinases; histone deacetylase; antitumor; synergistic effect; dual inhibitor
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Zhang, X.; Su, M.; Chen, Y.; Li, J.; Lu, W. The Design and Synthesis of a New Class of RTK/HDAC Dual-Targeted Inhibitors. Molecules 2013, 18, 6491-6503.

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