Degradation of HaloTag-fused nuclear proteins using bestatin-HaloTag ligand hybrid molecules

Organic & Biomolecular Chemistry
Shusuke TomoshigeMinoru Ishikawa

Abstract

We have developed a protein knockdown technology using hybrid small molecules designed as conjugates of a ligand for the target protein and a ligand for ubiquitin ligase cellular inhibitor of apoptosis protein 1 (cIAP1). However, this technology has several limitations. Here, we report the development of a novel protein knockdown system to address these limitations. In this system, target proteins are fused with HaloTag to provide a common binding site for a degradation inducer. We designed and synthesized small molecules consisting of alkyl chloride as the HaloTag-binding degradation inducer, which binds to HaloTag, linked to BE04 (2), which binds to cIAP1. Using this system, we successfully knocked down HaloTag-fused cAMP responsive element binding protein 1 (HaloTag-CREB1) and HaloTag-fused c-jun (HaloTag-c-jun), which are ligand-unknown nuclear proteins, in living cells. HaloTag-binding degradation inducers can be synthesized easily, and are expected to be useful as biological tools for pan-degradation of HaloTag-fused proteins.

References

Jul 5, 2001·Proceedings of the National Academy of Sciences of the United States of America·K M SakamotoR J Deshaies
Mar 25, 2004·Journal of the American Chemical Society·John S SchneeklothCraig M Crews
Nov 13, 2007·Nature Methods·Angelika Herm-GötzMarkus Meissner
Jan 31, 2008·The Journal of Biological Chemistry·Keiko SekineMikihiko Naito
Jun 7, 2008·ACS Chemical Biology·Georgyi V LosKeith V Wood
Oct 7, 2008·Nature Medicine·Laura A BanaszynskiSteve H Thorne
Nov 17, 2009·Nature Methods·Kohei NishimuraMasato Kanemaki
Dec 15, 2010·Nature Reviews. Drug Discovery·Lynn BedfordJames E Brownell
Apr 26, 2011·Bioorganic & Medicinal Chemistry·Yukihiro ItohYuichi Hashimoto
Jul 5, 2011·Nature Chemical Biology·Taavi K NeklesaCraig M Crews
Jul 5, 2011·Nature Chemical Biology·Kimberly M BongerThomas J Wandless
Oct 22, 2011·Bioorganic & Medicinal Chemistry·Yukihiro ItohYuichi Hashimoto
Jan 27, 2012·Bioorganic & Medicinal Chemistry Letters·Yosuke DemizuMasaaki Kurihara
Jun 5, 2012·Bioorganic & Medicinal Chemistry Letters·Yukihiro ItohYuichi Hashimoto
May 10, 2013·Annual Review of Biophysics·Ross C Wilson, Jennifer A Doudna
May 16, 2013·Proceedings of the National Academy of Sciences of the United States of America·John HinesCraig M Crews
Nov 5, 2013·ACS Chemical Biology·Kimberly M BongerThomas J Wandless
Oct 20, 2014·Nature Chemical Biology·Ting XieNathanael S Gray
Dec 31, 2014·Bioconjugate Chemistry·Shinichi SatoHiroyuki Nakamura
May 6, 2015·ACS Chemical Biology·Quentin DelacourArnaud Gautier
Jun 3, 2015·ACS Chemical Biology·Michael ZengerleAlessio Ciulli
Jun 9, 2015·Chemistry & Biology·Jing LuCraig M Crews
Jun 13, 2015·ACS Chemical Biology·Dennis L BuckleyCraig M Crews
Jun 16, 2015·Nature Chemical Biology·Daniel P BondesonCraig M Crews

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Citations

Sep 27, 2016·Bioorganic & Medicinal Chemistry Letters·Yosuke DemizuMasaaki Kurihara
May 2, 2017·Journal of Medicinal Chemistry·Koyo OkitsuYosuke Demizu
Nov 28, 2017·Annual Review of Genetics·Toyoaki Natsume, Masato T Kanemaki
Mar 5, 2019·Chemical & Pharmaceutical Bulletin·Norihito ShibataMikihiko Naito
Dec 14, 2019·Chembiochem : a European Journal of Chemical Biology·Samuel E Dalton, Sebastien Campos
Nov 26, 2016·Nature Reviews. Drug Discovery·Ashton C Lai, Craig M Crews
Jul 14, 2017·Angewandte Chemie·Shusuke TomoshigeMinoru Ishikawa
Oct 13, 2016·Annual Review of Pharmacology and Toxicology·Daniel P Bondeson, Craig M Crews
Sep 12, 2018·Scientific Reports·Norihito ShibataMikihiko Naito
Nov 22, 2019·Genome Biology·Zibo Zhao, Ali Shilatifard
Jun 17, 2020·Nature Structural & Molecular Biology·Tao WuEric S Fischer
Feb 23, 2020·Acta Pharmaceutica Sinica. B·Yang WangHaopeng Sun
Feb 1, 2020·Molecular Cell·Rati VermaRaymond J Deshaies
Nov 1, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jiangying CaoYingjie Zhang
May 26, 2021·Bioorganic & Medicinal Chemistry·Shusuke Tomoshige, Minoru Ishikawa
Jul 20, 2021·Journal of Medicinal Chemistry·Radosław P NowakEric S Fischer
Aug 5, 2017·Chemical Reviews·George M Burslem, Craig M Crews

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