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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 (CC BY 3.0).
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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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