- An Alkynylpyrimidine-Based Covalent Inhibitor That Targets a Unique Cysteine in NF-κB-Inducing Kinase
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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.
- Al-Khawaldeh, Islam,Al Yasiri, Mohammed J.,Aldred, Gregory G.,Basmadjian, Christine,Bordoni, Cinzia,Harnor, Suzannah J.,Heptinstall, Amy B.,Hobson, Stephen J.,Jennings, Claire E.,Khalifa, Shaimaa,Lebraud, Honorine,Martin, Mathew P.,Miller, Duncan C.,Shrives, Harry J.,de Souza, Jo?o V.,Stewart, Hannah L.,Temple, Max,Thomas, Huw D.,Totobenazara, Jane,Tucker, Julie A.,Tudhope, Susan J.,Wang, Lan Z.,Bronowska, Agnieszka K.,Cano, Céline,Endicott, Jane A.,Golding, Bernard T.,Hardcastle, Ian R.,Hickson, Ian,Wedge, Stephen R.,Willmore, Elaine,Noble, Martin E. M.,Waring, Michael J.
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supporting information
p. 10001 - 10018
(2021/07/26)
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- HETEROARYL OREXIN RECEPTOR ANTAGONISTS
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The present invention is directed to heteroaryl compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.
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Page/Page column 55
(2016/07/05)
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- AMINOPYRIMIDINES AS SYK INHIBITORS
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The present invention provides novel pyrimidine amines of formula (I) which are potent inhibitors of spleen tyrosine kinase, and are useful in the treatment and prevention of diseases mediated by said enzyme, such as asthma, COPD and rheumatoid arthritis.
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Page/Page column 55
(2011/07/07)
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- Conjugate addition of nucleophiles to the vinyl function of 2-chloro-4-vinylpyrimidine derivatives
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Conjugate addition reaction of various nucleophiles across the vinyl group of 2-chloro-4-vinylpyrimidine, 2-chloro-4-(1-phenylvinyl)pyrimidine and 2-chloro-4-vinylquinazoline provides the corresponding 2-chloro-4-(2-substituted ethyl)pyrimidines and 2-chl
- Raux, Elizabeth,Klenc, Jeffrey,Blake, Ava,Saczewski, Jaroslaw,Strekowski, Lucjan
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experimental part
p. 1973 - 1984
(2010/09/08)
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- Synthesis of 4-substituted 2-(4-methylpiperazino)pyrimidines and quinazoline analogs as serotonin 5-HT2A receptor ligands
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(Chemical Equation Presented) The addition reaction of lithium reagents to the 4 position of 2-chloropyrimidine or 2-chloroquinazoline followed by oxidation of the resultant dihydro intermediate product is a powerful tool for the synthesis of 4-substitute
- Saczewski, Jaroslaw,Paluchowska, Aldona,Klenc, Jeffrey,Raux, Elizabeth,Barnes, Samuel,Sullivan, Shannon,Duszynska, Beata,Bojarski, Andrzej J.,Strekowskia, Lucjan
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experimental part
p. 1259 - 1265
(2010/03/23)
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- Pyrimidinylpalladium(II) Complexes in the Synthesis of Alkenylpyrimidines
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Pyrimidinylpalladium(II) complexes have been prepared by oxidative addition of 4- and 5-halopyrimidines to tetrakis(triphenylphosphine)palladium(0) or tetrakis(triisopropyl phosphite)palladium(0).These complexes are used as catalysts in the synthesis of 4- and 5-alkenylpyrimidines from halopyrimidines and alkenylstannanes.
- Benneche, Tore
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p. 927 - 931
(2007/10/02)
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