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

// Lanlan Zang 1, * , Shukkoor M. Kondengaden 2, * , Qing Zhang 2, * , Xiaobo Li 5 , Dilep K. Sigalapalli 3 , Shameer M. Kondengadan 4 , Kenneth Huang 2 , Keqin Kathy Li 2 , Shanshan Li 2 , Zhongying Xiao 2 , Liuqing Wen 2 , Hailiang Zhu 2 , Bathini N. Babu 3 , Lijuan Wang 1 , Fengyuan Che 1 and Peng George Wang 2 1 Central Laboratory, Linyi People's Hospital, Linyi, Shandong 276003, P.R. China 2 Chemistry Department and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA 3 Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana 500037, India 4 Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Mohali, Punjab 160062, India 5 Department 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: pwang11@gsu.edu Fengyuan Che, email: che1971@126.com Lijuan Wang, email: lijian.wang730@outlook.com Keywords: epigenetics, pharmacophore, dual inhibitors, G9a inhibitors, HDAC inhibitors Received: April 14, 2017      Accepted: May 23, 2017      Published: June 28, 2017 ABSTRACT 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.