Al-Khawaldeh I

Aldred GG

Alyassiri M

Basmadjian C

Bordoni C

Bronowska AK

Cano C

de Souza JV

Endicott JA

Golding BT

Hardcastle IR

Harnor SJ

Heptinstall AB

Hickson I

Hobson SJ

Jennings CE

Khalifa S

Lebraud H

Miller DC

Noble MEM

Shrives HJ

Stewart HL

Temple M

Totobenazara J

Tucker JA

Tudhope SJ

Wang LZ

Waring MJ

Wedge SR

Willmore E

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

Newcastle University E-Prints

English

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

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

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