Laboratory for Epigenetics Drug Discovery
[Closed Mar. 2023]
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Epigenetics is a research field that tackles life information that is "added" to genetic information. The major entity of this "addition" is a chemical modification to a complex of a genomic DNA and histone proteins called chromatin. Since epigenetics is involved in the control of cancer, iPS cells and lifespan, it attracts attention as a molecular target for drug discovery, regenerative medicine, and anti-aging. Our laboratory aims to manipulate diseases, iPS cells and anti-aging as desired by developing technologies to precisely reconstitute, detect and control human epigenetic information.
Reconstitution of epigenetics
Synthetic technologies of a protein acetylated as designed. With this technology, transcriptionally active chromatin can be precisely reproduced in vitro.
Detection of epigenetics
Development of an antibody that detects acetylation at two residues in histone H4 tail. With this antibody, transcriptionally hyperactive chromatin can be detected at single nucleosome resolution.
Regulation of epigenetics
Histone demethylase inhibitor S2101 developed based on protein structure. This compound is commercially available as an epigenetics-regulating reagent.
Niwa H, Watanabe C, Sato S, et al.
Structure–activity relationship and in silico evaluation of cis- and trans-PCPA-derived inhibitors of LSD1 and LSD2.
ACS Medicinal Chemistry Letters 13, 1485-1492 (2022) doi: 10.1021/acsmedchemlett.2c00294
Kikuchi M, Morita S, Goto M, et al.
Elucidation of binding preferences of YEATS domains to site-specific acetylated nucleosome core particles.
Journal of Biological Chemistry 298, 102164 (2022) doi: 10.1016/j.jbc.2022.102164
Sasaki K, Suzuki M, Sonoda T, et al.
Visualization of the dynamic interaction between nucleosomal histone H3K9 tri-methylation and HP1α chromodomain in living cells.
Cell Chemical Biology 29, 1153-1161 (2022) doi: 10.1016/j.chembiol.2022.05.006
Koda Y, Sato S, Yamamoto H, et al.
Design and synthesis of tranylcypromine-derived LSD1 inhibitors with improved hERG and microsomal stability profiles.
ACS Medicinal Chemistry Letters 13, 848-854 (2022) doi: 10.1021/acsmedchemlett.2c00120
Kitagawa H, Kikuchi M, Sato S, et al.
Structure-based identification of potent lysine-specific demethylase 1 inhibitor peptides and temporary cyclization to enhance proteolytic stability and cell growth-inhibitory activity.
Journal of Medicinal Chemistry 64, 3707-3719 (2021) doi: 10.1021/acs.jmedchem.0c01371
Wakamori M, Okabe K, Ura K, et al.
Quantification of the effect of site-specific histone acetylation on chromatin transcription rate.
Nucleic Acids Research 48(22), 12648-12659 (2020) doi: 10.1093/nar/gkaa1050
Wu HD, Kikuchi M, Dagliyan O, et al.
Rational design and implementation of a chemically inducible hetero-trimerization system.
Nature Methods 17, 928-936 (2020) doi: 10.1038/s41592-020-0913-x
Furukawa A, Wakamori M, Arimura Y, et al.
Acetylated histone H4 tail enhances histone H3 tail acetylation by altering their mutual dynamics in the nucleosome.
Proceedings of the National Academy of Sciences USA 117, 19661-19663 (2020) doi: 10.1073/pnas.2010506117
Saito S, Kikuchi J, Koyama D, et al.
Eradication of central nervous system leukemia of T-cell origin with a brain-permeable LSD1 inhibitor.
Clinical Cancer Research 25, 1601-1611 (2019) doi: 10.1158/1078-0432.CCR-18-0919
Handoko L, Kaczkowski B, Hon CC, et al.
JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states.
Epigenetics 13, 410-431 (2018) doi: 10.1080/15592294.2018.1469891
Team LeaderTakashi Umehara
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Senior Technical Scientist*Hideaki Niwa
Research ScientistMasaki Kikuchi
Research ScientistNando Dulal Das
Technical ScientistSatoshi Morita
Technical ScientistMasatoshi Wakamori
Technical ScientistShin Sato
Technical ScientistHisami Watanabe
Research FellowDaisuke Aoki
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