title: Identification of Novel Disruptor of Telomeric Silencing 1-like (DOT1L) Inhibitors through Structure-Based Virtual Screening and Biological Assays.
abstract: Histone methyltransferases are involved in many important biological processes, and abnormalities in these enzymes are associated with tumorigenesis and progression. Disruptor of telomeric silencing 1-like (DOT1L), a key hub in histone lysine methyltransferases, has been reported to play an important role in the processes of mixed-lineage leukemia (MLL)-rearranged leukemias and validated to be a potential therapeutic target. In this study, we identified a novel DOT1L inhibitor, DC_L115 (CAS no. 1163729-79-0), by combining structure-based virtual screening with biochemical analyses. This potent inhibitor DC_L115 shows high inhibitory activity toward DOT1L (IC50 = 1.5 μM). Through a process of surface plasmon resonance-based binding assays, DC_L115 was founded to bind to DOT1L with a binding affinity of 0.6 μM in vitro. Moreover, this compound selectively inhibits MLL-rearranged cell proliferation with an IC50 value of 37.1 μM. We further predicted the binding modes of DC_L115 through molecular docking analysis and found that the inhibitor competitively occupies the binding site of S-adenosylmethionine. Overall, this study demonstrates the development of potent DOT1L inhibitors with novel scaffolds.
authors.affiliation: School of Life Science and Technology, Shanghai Tech University , Shanghai 200031, China.|Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chongzhi Road, Shanghai 201203, China.
authors.forename: Shijie
authors.initials: S
authors.lastname: Chen
authors.affiliation: School of Life Science and Technology, Shanghai Tech University , Shanghai 200031, China.|Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chongzhi Road, Shanghai 201203, China.
authors.forename: Linjuan
authors.initials: L
authors.lastname: Li
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chongzhi Road, Shanghai 201203, China.
authors.forename: Yantao
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chongzhi Road, Shanghai 201203, China.
authors.forename: Junchi
authors.initials: J
authors.lastname: Hu
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chongzhi Road, Shanghai 201203, China.
authors.forename: Jingqiu
authors.initials: J
authors.lastname: Liu
authors.affiliation: In Vitro Biology, Shanghai ChemPartner LifeScience Co., Ltd. , #5 Building, 998 Halei Road, Shanghai 201203, China.
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Liu
authors.affiliation: In Vitro Biology, Shanghai ChemPartner LifeScience Co., Ltd. , #5 Building, 998 Halei Road, Shanghai 201203, China.
authors.forename: Rongfeng
authors.initials: R
authors.lastname: Liu
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chongzhi Road, Shanghai 201203, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chongzhi Road, Shanghai 201203, China.
authors.forename: Fanwang
authors.initials: F
authors.lastname: Meng
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chongzhi Road, Shanghai 201203, China.
authors.forename: Kongkai
authors.initials: K
authors.lastname: Zhu
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chongzhi Road, Shanghai 201203, China.
authors.forename: Junyan
authors.initials: J
authors.lastname: Lu
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chongzhi Road, Shanghai 201203, China.
authors.forename: Mingyue
authors.initials: M
authors.lastname: Zheng
authors.affiliation: School of Life Science and Technology, Shanghai Tech University , Shanghai 200031, China.|Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chongzhi Road, Shanghai 201203, China.
authors.forename: Kaixian
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai 200127, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: School of Life Science and Technology, Shanghai Tech University , Shanghai 200031, China.|Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chongzhi Road, Shanghai 201203, China.
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.affiliation: College of Chemical and Environmental Engineering, Shanghai Institute of Technology , Shanghai 210032, China.
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chongzhi Road, Shanghai 201203, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
mesh_terms: D020868:Gene Silencing; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D008780:Methyltransferases / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D020349:Surface Plasmon Resonance; D016615:Telomere
chemical_list: C473477:DOT1L protein, human; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase