Research Project
Grant-in-Aid for Scientific Research (B)
Based on our protein knockdown technology, we developed a number of Specific and Nongenetic IAP-dependent Protein Erasers (SNIPERs) that can induce the ubiquitylation and proteasomal degradation of estrogen receptor-alpha, androgen receptor, BCR-ABL, BRD4 and His-tagged proteins etc. We demonstrated that SNIPERs can target cytosolic, nuclear and membrane-anchored proteins for degradation, and clarified the degradation mechanism of target proteins and IAPs. We also showed that SNIPER against BCR-ABL protein can exhibit a potent anti-cancer effect even after the drug removal, which contrasts a kinase inhibitor whose anti-cancer effect diminished immediately after the drug removal. Protein degradation by SNIPERs can show pharmacologically different effects as compared with functional inhibitors.
SNIPER技術は研究代表者らが開発した独自技術であり、細胞内で標的タンパク質のユビキチン修飾が引き起こす直接的な影響を解析する事ができる。本研究で開発したSNIPER化合物を利用して学術的にも有意義な新しい知見が得られる可能性がある。またこの技術では任意の標的タンパク質を特異的に分解するSNIPER化合物を合理的に開発する事ができ、従来技術では阻害剤を開発する事が難しい標的タンパク質を狙って分解するSNIPERを開発する事も期待される。新しい創薬技術としても有望であり、社会的意義も高い。
All 2019 2018 2017 2016 Other
All Journal Article (18 results) (of which Int'l Joint Research: 9 results, Peer Reviewed: 18 results, Open Access: 7 results, Acknowledgement Compliant: 5 results) Presentation (36 results) (of which Int'l Joint Research: 5 results, Invited: 15 results) Remarks (2 results)
Chemical and Pharmaceutical Bulletin
Volume: 67 Issue: 3 Pages: 203-209
10.1248/cpb.c18-00567
130007607114
Volume: 67 Issue: 3 Pages: 165-172
10.1248/cpb.c18-00703
130007606378
Drug Discovery Today: Technology
Volume: 印刷中 Pages: 481-488
10.1016/j.ddtec.2018.12.002
Scientific Reports
Volume: 8 Issue: 1 Pages: 13549-13549
10.1038/s41598-018-31913-5
Journal of Biological Chemistry
Volume: 293 Issue: 18 Pages: 6776-6790
10.1074/jbc.ra117.001091
J Med Chem.
Volume: 61 Issue: 2 Pages: 576-582
10.1021/acs.jmedchem.7b00413
Bioorg. Med. Chem. Lett.
Volume: 27 Issue: 18 Pages: 4478-4481
10.1016/j.bmcl.2017.08.001
Cancer Sci
Volume: 108 Issue: 5 Pages: 1032-1041
10.1111/cas.13198
Bioorg Med Chem Lett.
Volume: 27 Issue: 22 Pages: 4985-4988
10.1016/j.bmcl.2017.10.011
Cancer Science
Volume: 108 Issue: 8 Pages: 1657-1666
10.1111/cas.13284
Journal of Medicinal Chemistry
Volume: 61 Issue: 2 Pages: 543-575
10.1021/acs.jmedchem.7b00168
ACS Medicinal Chemistry Letters
Volume: 8 Issue: 10 Pages: 1042-1047
10.1021/acsmedchemlett.7b00247
Bioorg Med Chem.
Volume: 25(6) Issue: 6 Pages: 1846-1851
10.1016/j.bmc.2017.01.044
Mol pharmacol
Volume: 91 Issue: 3 Pages: 159-166
10.1124/mol.116.105569
J Biol Chem
Volume: 292 Issue: 11 Pages: 4556-4570
10.1074/jbc.m116.768853
Methods Mol. Biol.
Volume: 1366 Pages: 549-560
10.1007/978-1-4939-3127-9_42
Curr Cancer Drug Targets
Volume: 16 Pages: 136-146
Bioorg Med Chem Lett
Volume: 26 Issue: 20 Pages: 4865-4869
10.1016/j.bmcl.2016.09.041
http://www.nihs.go.jp/mtgt/research.html