Structure based design, synthesis and activity studies of small hybrid molecules as HDAC and G9a dual inhibitors
Metrics: PDF 1683 views | HTML 3400 views | ?
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
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.