Research Papers:

Structure based design, synthesis and activity studies of small hybrid molecules as HDAC and G9a dual inhibitors

Lanlan Zang, Shukkoor M. Kondengaden, Qing Zhang, Xiaobo Li, Dilep K. Sigalapalli, Shameer M. Kondengadan, Kenneth Huang, Keqin Kathy Li, Shanshan Li, Zhongying Xiao, Liuqing Wen, Hailiang Zhu, Bathini N. Babu, Lijuan Wang, Fengyuan Che and Peng George Wang _

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Oncotarget. 2017; 8:63187-63207. https://doi.org/10.18632/oncotarget.18730

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Lanlan Zang1,*, Shukkoor M. Kondengaden2,*, Qing Zhang2,*, Xiaobo Li5, Dilep K. Sigalapalli3, Shameer M. Kondengadan4, Kenneth Huang2, Keqin Kathy Li2, Shanshan Li2, Zhongying Xiao2, Liuqing Wen2, Hailiang Zhu2, Bathini N. Babu3, Lijuan Wang1, Fengyuan Che1 and Peng George Wang2

1Central Laboratory, Linyi People's Hospital, Linyi, Shandong 276003, P.R. China

2Chemistry Department and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA

3Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana 500037, India

4Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Mohali, Punjab 160062, India

5Department of Immunology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin 300070, P.R. China

*These authors have contributed equally to this work

Correspondence to:

Peng George Wang, email: [email protected]

Fengyuan Che, email: [email protected]

Lijuan Wang, email: [email protected]

Keywords: epigenetics, pharmacophore, dual inhibitors, G9a inhibitors, HDAC inhibitors

Received: April 14, 2017     Accepted: May 23, 2017     Published: June 28, 2017


Aberrant enzymatic activities or expression profiles of epigenetic regulations are therapeutic targets for cancers. Among these, histone 3 lysine 9 methylation (H3K9Me2) and global de-acetylation on histone proteins are associated with multiple cancer phenotypes including leukemia, prostatic carcinoma, hepatocellular carcinoma and pulmonary carcinoma. Here, we report the discovery of the first small molecule capable of acting as a dual inhibitor targeting both G9a and HDAC. Our structure based design, synthesis, and screening for the dual activity of the small molecules led to the discovery of compound 14 which displays promising inhibition of both G9a and HDAC in low micro-molar range in cell based assays.

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