PROTAC-Mediated Degradation of Bruton's Tyrosine Kinase Is Inhibited by Covalent Binding

ACS Chemical Biology
Christopher P TinworthJohn D Harling

Abstract

The impact of covalent binding on PROTAC-mediated degradation of BTK was investigated through the preparation of both covalent binding and reversible binding PROTACs derived from the covalent BTK inhibitor ibrutinib. It was determined that a covalent binding PROTAC inhibited BTK degradation despite evidence of target engagement, while BTK degradation was observed with a reversible binding PROTAC. These observations were consistently found when PROTACs that were able to recruit either IAP or cereblon E3 ligases were employed. Proteomics analysis determined that the use of a covalently bound PROTAC did not result in the degradation of covalently bound targets, while degradation was observed for some reversibly bound targets. This observation highlights the importance of catalysis for successful PROTAC-mediated degradation and highlights a potential caveat for the use of covalent target binders in PROTAC design.

References

Mar 3, 1999·Proceedings of the National Academy of Sciences of the United States of America·S NisitaniM I Wahl
Dec 18, 2002·The Journal of Experimental Medicine·Tomás BrdickaVáclav Horejsí
Aug 18, 2004·Nature Structural & Molecular Biology·Sumit PrakashAndreas Matouschek
Jan 31, 2008·The Journal of Biological Chemistry·Keiko SekineMikihiko Naito
Jul 10, 2010·Proceedings of the National Academy of Sciences of the United States of America·Lee A HonigbergJoseph J Buggy
Jun 24, 2014·Autoimmunity·Yuekang XuDavid M Tarlinton
Apr 8, 2015·Organic & Biomolecular Chemistry·Nora LiuHerman S Overkleeft
Jun 13, 2015·ACS Chemical Biology·Dennis L BuckleyCraig M Crews
Jun 16, 2015·Nature Chemical Biology·Daniel P BondesonCraig M Crews
Jan 13, 2016·Angewandte Chemie·Momar Toure, Craig M Crews
Mar 24, 2016·Cell Research·Xiaodong Huang, Vishva M Dixit
Jun 9, 2016·Proceedings of the National Academy of Sciences of the United States of America·Kanak RainaKevin G Coleman
Jan 7, 2017·ACS Central Science·Honorine LebraudTom D Heightman
Jun 24, 2017·Nature Reviews. Cancer·Chi V DangLaura Soucek
Sep 7, 2017·ACS Chemical Biology·Lars DittusMarcus Bantscheff
Nov 14, 2017·Cell Chemical Biology·Hai-Tsang HuangNathanael S Gray
Nov 14, 2017·Cell Chemical Biology·Daniel P BondesonCraig M Crews
Jul 18, 2018·Proceedings of the National Academy of Sciences of the United States of America·Adelajda ZorbaMatthew F Calabrese

❮ Previous
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Citations

Nov 2, 2019·Nature Reviews. Drug Discovery·Matthieu SchapiraCraig M Crews
Nov 9, 2019·Future Medicinal Chemistry·Li-Wen XiaYong-Tao Duan
Nov 23, 2019·Chemical Communications : Chem Comm·Xuan ZhangGuangrong Zheng
Jun 19, 2019·Current Topics in Medicinal Chemistry·Yongtao DuanChuanjun Song
Dec 14, 2019·Chembiochem : a European Journal of Chemical Biology·Samuel E Dalton, Sebastien Campos
Jan 11, 2020·Chemical Communications : Chem Comm·Gang XueZhengying Pan
Sep 15, 2020·Exploration of Targeted Anti-tumor Therapy·Rachael ArthurGraham Packham
Sep 17, 2020·Journal of Experimental & Clinical Cancer Research : CR·Alberto Ocaña, Atanasio Pandiella
May 20, 2020·Angewandte Chemie·Laura M LuhPhilipp M Cromm
May 15, 2020·Journal of Hematology & Oncology·Xin Li, Yongcheng Song
Jun 17, 2020·Nature Structural & Molecular Biology·Tao WuEric S Fischer
Dec 24, 2019·MedChemComm·Hannah J MapleRobert Felix
Jun 9, 2020·Acta Biochimica Et Biophysica Sinica·Yilin Chen, Jianping Jin
Nov 2, 2019·MedChemComm·Eric ValeurAlleyn T Plowright
Nov 24, 2020·Organic & Biomolecular Chemistry·Haixia LiuBiao Jiang
Nov 9, 2020·European Journal of Medicinal Chemistry·Shenxin ZengZhengrong Shen
Dec 31, 2019·Cell Chemical Biology·Mei ZengNathanael S Gray
Jan 7, 2020·Current Opinion in Chemical Biology·Alexander Hanzl, Georg E Winter
Nov 1, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jiangying CaoYingjie Zhang
Dec 20, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Bernat Coll-MartínezBernat Crosas
Nov 18, 2020·Nature Chemical Biology·James SchiemerMatthew F Calabrese
Feb 8, 2021·Current Opinion in Chemical Biology·Ronen Gabizon, Nir London
Feb 25, 2021·Journal of Chemical Information and Modeling·Nan BaiJohn Karanicolas
Feb 21, 2021·Bioorganic & Medicinal Chemistry Letters·Jiamin ZhengGe Zou
May 1, 2020·Journal of Medicinal Chemistry·Emily J HananSteven T Staben
Sep 1, 2020·Biochemical Pharmacology·Yuqing LiangKui Cheng
Apr 1, 2021·Cell Chemical Biology·Hannah Kiely-CollinsGonçalo J L Bernardes
Mar 30, 2021·Frontiers in Chemistry·Shenxin ZengWenhai Huang
Mar 29, 2021·European Journal of Medicinal Chemistry·Chao WangPing Xu
Apr 28, 2021·Trends in Pharmacological Sciences·Paul Gehrtz, Nir London
Jul 20, 2021·Frontiers in Chemistry·Fei YuJihong Zhang
Jul 25, 2021·International Journal of Molecular Sciences·Chiara BrulloAndrea Spallarossa
Aug 6, 2021·Frontiers in Cell and Developmental Biology·Jing LiuWenyi Wei
Aug 7, 2021·Nature Reviews. Drug Discovery·Misty M AttwoodHelgi B Schiöth
May 6, 2020·Journal of the American Chemical Society·Ronen GabizonNir London
Aug 20, 2021·European Journal of Medicinal Chemistry·Chao WangDongming Xing
Aug 17, 2020·Cell Chemical Biology·Dhanusha A Nalawansha, Craig M Crews
Sep 21, 2019·Biochemistry·Yiqing Zhou, Youli Xiao
Sep 3, 2020·ACS Central Science·Elena De VitaEdward W Tate
Sep 25, 2020·Journal of Chemical Information and Modeling·Michael L DrummondChristopher I Williams
Sep 8, 2021·Journal of Hematology & Oncology·Haobin LiJiang-Jiang Qin
Sep 9, 2021·Chembiochem : a European Journal of Chemical Biology·Zhenyi Hu, Craig M Crews

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