An Alkynylpyrimidine-Based Covalent Inhibitor That Targets a Unique Cysteine in NF-?B-Inducing Kinase

نویسندگان

چکیده

NF-?B-inducing kinase (NIK) is a key enzyme in the noncanonical NF-?B pathway, of interest treatment variety diseases including cancer. Validation NIK as drug target requires potent and selective inhibitors. The protein contains cysteine residue at position 444 back pocket active site, unique within kinome. Analysis existing inhibitor scaffolds early structure-activity relationships (SARs) led to design C444-targeting covalent inhibitors based on alkynyl heterocycle warheads. Mass spectrometry provided proof mechanism, SAR was rationalized by computational modeling. Profiling more analogues tumor cell lines with constitutively activated signaling induced weak antiproliferative effect, suggesting that inhibition may have limited impact cancer growth. This study shows heterocycles are potential traps, which be employed where common Michael acceptors, such acrylamides, not tolerated.

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ژورنال

عنوان ژورنال: Journal of Medicinal Chemistry

سال: 2021

ISSN: ['0022-2623', '1520-4804']

DOI: https://doi.org/10.1021/acs.jmedchem.0c01249