An Alkynylpyrimidine-Based Covalent Inhibitor That Targets a Unique Cysteine in NF-κB-Inducing Kinase.

Autor:	Al-Khawaldeh I; Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K., Al Yasiri MJ; Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K., Aldred GG; Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K., Basmadjian C; Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K., Bordoni C; Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K., Harnor SJ; Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K., Heptinstall AB; Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K., Hobson SJ; Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K., Jennings CE; Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Paul O'Gorman Building, Newcastle upon Tyne NE2 4HH, U.K., Khalifa S; Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K., Lebraud H; Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K., Martin MP; Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Paul O'Gorman Building, Newcastle upon Tyne NE2 4HH, U.K., Miller DC; Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K., Shrives HJ, de Souza JV; Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K., Stewart HL; Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K., Temple M; Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Paul O'Gorman Building, Newcastle upon Tyne NE2 4HH, U.K., Thomas HD; Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Paul O'Gorman Building, Newcastle upon Tyne NE2 4HH, U.K., Totobenazara J; Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K., Tucker JA; Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Paul O'Gorman Building, Newcastle upon Tyne NE2 4HH, U.K., Tudhope SJ; Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Paul O'Gorman Building, Newcastle upon Tyne NE2 4HH, U.K., Wang LZ; Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Paul O'Gorman Building, Newcastle upon Tyne NE2 4HH, U.K., Bronowska AK; Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K., Cano C; Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K., Endicott JA; Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Paul O'Gorman Building, Newcastle upon Tyne NE2 4HH, U.K., Golding BT; Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K., Hardcastle IR; Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K., Hickson I; Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Paul O'Gorman Building, Newcastle upon Tyne NE2 4HH, U.K., Wedge SR; Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Paul O'Gorman Building, Newcastle upon Tyne NE2 4HH, U.K., Willmore E; Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Paul O'Gorman Building, Newcastle upon Tyne NE2 4HH, U.K., Noble MEM; Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Paul O'Gorman Building, Newcastle upon Tyne NE2 4HH, U.K., Waring MJ; Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2021 Jul 22; Vol. 64 (14), pp. 10001-10018. Date of Electronic Publication: 2021 Jul 02.
DOI:	10.1021/acs.jmedchem.0c01249
Abstrakt:	NF-κB-inducing kinase (NIK) is a key enzyme in the noncanonical NF-κB pathway, of interest in the treatment of a variety of diseases including cancer. Validation of NIK as a drug target requires potent and selective inhibitors. The protein contains a cysteine residue at position 444 in the back pocket of the active site, unique within the kinome. Analysis of existing inhibitor scaffolds and early structure-activity relationships (SARs) led to the design of C444-targeting covalent inhibitors based on alkynyl heterocycle warheads. Mass spectrometry provided proof of the covalent mechanism, and the SAR was rationalized by computational modeling. Profiling of more potent analogues in tumor cell lines with constitutively activated NIK signaling induced a weak antiproliferative effect, suggesting that kinase inhibition may have limited impact on cancer cell growth. This study shows that alkynyl heterocycles are potential cysteine traps, which may be employed where common Michael acceptors, such as acrylamides, are not tolerated.
Databáze:	MEDLINE
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