title: Discovery of novel small molecule inhibitors of lysine methyltransferase G9a and their mechanism in leukemia cell lines.
abstract: Lysine methyltransferase G9a regulates the transcription of multiple genes by primarily catalyzing mono- and di-methylation of histone H3 lysine 9, as well as several non-histone lysine sites. An attractive therapeutic target in treating leukemia, knockout studies of G9a in mice have found dramatically slowed proliferation and self-renewal of acute myeloid leukemia (AML) cells due to the attenuation of HoxA9-dependent transcription. In this study, a series of compounds were identified as potential inhibitors through structure-based virtual screening. Among these compounds, a new G9a inhibitor, DCG066, was confirmed by in vitro biochemical, and cell based enzyme assays. DCG066 has a novel molecular scaffold unlike other G9a inhibitors presently available. Similar to G9a's histone substrate, DCG066 can bind directly to G9a and inhibit methyltransferase activity in vitro. In addition to suppressing G9a methyltransferase activity and reducing histone H3 methylation levels, DCG066 displays low cytotoxicity in leukemia cell lines with high levels of G9a expression, including K562. This work presents DCG066 as an inhibitor of G9a with a novel structure, providing both a lead in G9a inhibitor design and a means for probing the functionality of G9a.
authors.affiliation: Chemistry Department and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA.
authors.forename: Shukkoor M
authors.initials: SM
authors.lastname: Kondengaden
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Liu-Fei
authors.initials: LF
authors.lastname: Luo
authors.affiliation: Chemistry Department and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Huang
authors.affiliation: Chemistry Department and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA.
authors.forename: Mengyuan
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Chemistry Department and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA; Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Lanlan
authors.initials: L
authors.lastname: Zang
authors.affiliation: Chemistry Department and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA.
authors.forename: Eudoxie
authors.initials: E
authors.lastname: Bataba
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Runling
authors.initials: R
authors.lastname: Wang
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
authors.affiliation: Chemistry Department and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA.
authors.forename: Binghe
authors.initials: B
authors.lastname: Wang
authors.affiliation: Chemistry Department and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA; State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University, Shanghai, China. Electronic address: kli10@gsu.edu.
authors.forename: Keqin Kathy
authors.initials: KK
authors.lastname: Li
authors.affiliation: Chemistry Department and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA. Electronic address: pwang11@gsu.edu.
authors.forename: Peng George
authors.initials: PG
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001381:Azepines / Q000378:metabolism; D001667:Binding, Competitive; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D055808:Drug Discovery; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D051379:Mice; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D011799:Quinazolines / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D001381:Azepines; C518299:BIX 01294; D011799:Quinazolines; D054852:Small Molecule Libraries; D011495:Histone-Lysine N-Methyltransferase
keywords: G9a inhibitor; Leukemia; Lysine methyltransferase; MALDI-TOF assay; PMPKMTDYPOAEEH-UHFFFAOYSA-N