An Alkynylpyrimidine-Based Covalent Inhibitor That Targets a Unique Cysteine in NF-κB-Inducing Kinase
| Autor: | Lan Z. Wang, Miller Duncan Charles, Bernard T. Golding, Ian Hickson, Martin E.M. Noble, Celine Cano, Suzannah J. Harnor, Michael J. Waring, Harry J Shrives, Shaimaa Khalifa, Jane Totobenazara, Stephen J. Hobson, Elaine Willmore, Hannah L Stewart, Mathew P. Martin, Susan J. Tudhope, Huw D. Thomas, Islam Al-Khawaldeh, Claire E. Jennings, João V de Souza, Max J. Temple, Jane A. Endicott, Cinzia Bordoni, Honorine Lebraud, Agnieszka K. Bronowska, Ian R. Hardcastle, Amy B. Heptinstall, Stephen R. Wedge, Christine Basmadjian, Gregory G Aldred, Julie A. Tucker, Mohammed J Al Yasiri |
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| Rok vydání: | 2021 |
| Předmět: |
chemistry.chemical_classification
Dose-Response Relationship Drug Molecular Structure biology Chemistry Kinase Active site Protein Serine-Threonine Kinases Structure-Activity Relationship Residue (chemistry) Pyrimidines Enzyme Biochemistry Covalent bond Alkynes Drug Discovery Cancer cell biology.protein Humans Molecular Medicine Kinome Cysteine Protein Kinase Inhibitors |
| Zdroj: | Journal of Medicinal Chemistry. 64:10001-10018 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.0c01249 |
| Popis: | 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: | OpenAIRE |
| Externí odkaz: |
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