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

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

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

Afiliação

Zang L; Central Laboratory, Linyi People's Hospital, Linyi, Shandong 276003, P.R. China.
Kondengaden SM; Chemistry Department and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA.
Zhang Q; Chemistry Department and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA.
Li X; 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.
Sigalapalli DK; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana 500037, India.
Kondengadan SM; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Mohali, Punjab 160062, India.
Huang K; Chemistry Department and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA.
Li KK; Chemistry Department and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA.
Li S; Chemistry Department and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA.
Xiao Z; Chemistry Department and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA.
Wen L; Chemistry Department and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA.
Zhu H; Chemistry Department and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA.
Babu BN; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana 500037, India.
Wang L; Central Laboratory, Linyi People's Hospital, Linyi, Shandong 276003, P.R. China.
Che F; Central Laboratory, Linyi People's Hospital, Linyi, Shandong 276003, P.R. China.
Wang PG; Chemistry Department and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA.

Oncotarget ; 8(38): 63187-63207, 2017 Sep 08.

Article em En | MEDLINE | ID: mdl-28968981

ABSTRACT

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.

Palavras-chave

G9a inhibitors; HDAC inhibitors; dual inhibitors; epigenetics; pharmacophore

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