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

Molecules

Xuan Zhang²  Mingbo Su¹  Yi Chen³  Jia Li³ 

[1] School of Life Sciences, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China; E-Mail:;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; E-Mail:;State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, SIBS, Chinese Academy of Sciences, Shanghai 201203, China; E-Mails:

关键词: receptor tyrosine kinases;    histone deacetylase;    antitumor;    synergistic effect;    dual inhibitor;   

DOI  :  10.3390/molecules18066491

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2013 by the authors; licensee MDPI, Basel, Switzerland.