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An alkynylpyrimidine-based covalent inhibitor that targets a unique cysteine in NF-κB-inducing kinase (NIK)

Lookup NU author(s): Islam Al-Khawaldeh, Dr Christine Basmadjian, Dr Cinzia Bordoni, Dr Suzannah HarnorORCiD, Amy Heptinstall, Dr Stephen Hobson, Dr Claire Jennings, Shaimaa Khalifah, Honorine Lebraud, Duncan MillerORCiD, Dr Harry Shrives, Joao Victor de De Souza Cunha, Dr Hannah Stewart, Dr Max Temple, Dr Jane Totobenazara, Julie Tucker, Dr Susan Tudhope, Lan Wang, Dr Agnieszka Bronowska, Dr Celine CanoORCiD, Professor Jane Endicott, Emeritus Professor Bernard Golding, Dr Ian HardcastleORCiD, Professor Ian HicksonORCiD, Professor Steve Wedge, Dr Elaine WillmoreORCiD, Professor Martin NobleORCiD, Professor Mike Waring



This is the authors' accepted manuscript of an article that has been published in its final definitive form by American Chemical Society , 2021.

For re-use rights please refer to the publisher's terms and conditions.


NF-κB-inducing kinase is a key enzyme in the noncanonical NF-κB pathway and its inhibition is of potential interest in the treatment of a variety of diseases including inflammation and cancer. Validation of NF-κB-inducing kinase as a drug target requires the development of potent and selective inhibitors. The protein contains a cysteine residue at position 444 in the back pocket of the active site, which is unique within the kinome. An analysis of existing inhibitor scaffolds and early structure activity relationships for analogues led to the design of covalent inhibitors based on alkynyl heterocycle covalent warheads. Proof of their covalent mechanism was provided by mass spectrometry and SAR was rationalised by computational modelling. Further profiling of more potent analogues in tumour cell lines with constitutively activated NF-κB-inducing kinase signaling induced a weak antiproliferative effect, suggesting that inhibition of its kinase activity may have limited impact on cancer cell growth. This work shows that alkynyl heterocycles are potential cysteine traps, which may be employed where common Michael acceptors, such as acrylamides, are not tolerated.

Publication metadata

Author(s): Al-Khawaldeh I, Aldred GG, Alyassiri M, Basmadjian C, Bordoni C, Harnor SJ, Heptinstall AB, Hobson SJ, Jennings CE, Khalifa S, Lebraud H, Miller DC, Shrives HJ, de Souza JV, Stewart HL, Temple M, Totobenazara J, Tucker JA, Tudhope SJ, Wang LZ, Bronowska AK, Cano C, Endicott JA, Golding BT, Hardcastle IR, Hickson I, Wedge SR, Willmore E, Noble MEM, Waring MJ

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 2021

Volume: 64

Issue: 14

Pages: 10001-10018

Print publication date: 22/07/2021

Online publication date: 02/07/2021

Acceptance date: 21/06/2021

Date deposited: 05/07/2021

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

Publisher: American Chemical Society


DOI: 10.1021/acs.jmedchem.0c01249


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