Discovery of novel DNA methyltransferase 3A inhibitors via structure-based virtual screening and biological assays

Zhiyuan Shao; Pan Xu; Wen Xu; Linjuan Li; Shien Liu; Rukang Zhang; Yu-Chih Liu; Chenhua Zhang; Shijie Chen; Cheng Luo

doi:10.1016/j.bmcl.2016.11.023

Discovery of novel DNA methyltransferase 3A inhibitors via structure-based virtual screening and biological assays

Bioorg Med Chem Lett. 2017 Jan 15;27(2):342-346. doi: 10.1016/j.bmcl.2016.11.023. Epub 2016 Nov 11.

Authors

Zhiyuan Shao¹, Pan Xu², Wen Xu³, Linjuan Li⁴, Shien Liu², Rukang Zhang⁴, Yu-Chih Liu⁵, Chenhua Zhang⁵, Shijie Chen⁶, Cheng Luo⁷

Affiliations

¹ Nano Science and Technology Institute, University of Science and Technology of China, Suzhou 215123, China.
² Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of MateriaMedica, Chinese Academy of Sciences, Shanghai 201203, China.
³ Obstetrics & Gynecology Hospital of Fudan University, No. 419 Fangxie Road, Shanghai 200011, China.
⁴ Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of MateriaMedica, Chinese Academy of Sciences, Shanghai 201203, China; School of Life Science and Technology, Shanghai Tech University, Shanghai 200031, China.
⁵ Shanghai ChemPartner Co., LTD, Building 5, 998, Halei Road, Zhangjiang Hi-Tech Park, Pudong New Area, Shanghai 201203, China.
⁶ Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of MateriaMedica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: [email protected].
⁷ Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of MateriaMedica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: [email protected].

PMID: 27899265
DOI: 10.1016/j.bmcl.2016.11.023

Abstract

DNA methyltransferases are involved in diverse biological processes and abnormal methylation patterns play essential roles in cancer initiation and progression. DNA methyltransferase 3A (DNMT3A) acting as a de novo DNA methyltransferase, has gained widespread attention especially in haematological diseases. To date, large numbers of DNMTs inhibitors have been discovered, however, the small molecular inhibitors targeting DNMT3A are still in its infancy. In this study, structure-based virtual screening in combination with biological assays was performed to discovery potent novel DNMT3A inhibitors. Compound 40 and 40_3 displayed comparable in vitro inhibitory activity against DNMT3A with IC₅₀ values of 46.5μM and 41μM, respectively. Further binding mode analysis suggested these molecules inhibit DNMT3A activity through binding the S-adenosyl-l-methionine (SAM) pocket. Overall, 40 and 40_3 may serve as novel scaffolds for further optimization and small molecular probes for investigating DNMT3A function.

Keywords: DNMT3A inhibitors; Epigenetics; Molecular docking; Virtual screening.

MeSH terms

Cell Line
DNA (Cytosine-5-)-Methyltransferases / antagonists & inhibitors*
DNA (Cytosine-5-)-Methyltransferases / metabolism
DNA Methyltransferase 3A
Dose-Response Relationship, Drug
Drug Discovery*
Drug Evaluation, Preclinical
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Molecular Docking Simulation
Molecular Structure
Structure-Activity Relationship

Substances

DNMT3A protein, human
Enzyme Inhibitors
DNA (Cytosine-5-)-Methyltransferases
DNA Methyltransferase 3A