2. Academic Validation
  3. An Alkynylpyrimidine-Based Covalent Inhibitor That Targets a Unique Cysteine in NF-κB-Inducing Kinase

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

  • J Med Chem. 2021 Jul 22;64(14):10001-10018. doi: 10.1021/acs.jmedchem.0c01249.
Islam Al-Khawaldeh 1,  Mohammed J Al Yasiri 1,  Gregory G Aldred 1,  Christine Basmadjian 1,  Cinzia Bordoni 1,  Suzannah J Harnor 1,  Amy B Heptinstall 1,  Stephen J Hobson 1,  Claire E Jennings 2,  Shaimaa Khalifa 1,  Honorine Lebraud 1,  Mathew P Martin 2,  Duncan C Miller 1,  Harry J Shrives,  João V de Souza 3,  Hannah L Stewart 1,  Max Temple 2,  Huw D Thomas 2,  Jane Totobenazara 1,  Julie A Tucker 2,  Susan J Tudhope 2,  Lan Z Wang 2,  Agnieszka K Bronowska 3,  Céline Cano 1,  Jane A Endicott 2,  Bernard T Golding 3,  Ian R Hardcastle 1,  Ian Hickson 2,  Stephen R Wedge 2,  Elaine Willmore 2,  Martin E M Noble 2,  Michael J Waring 1
Affiliations

Affiliations

  • 1 Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.
  • 2 Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Paul O'Gorman Building, Newcastle upon Tyne NE2 4HH, U.K.
  • 3 Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.
PMID: 34212719 DOI: 10.1021/acs.jmedchem.0c01249
Abstract

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-153516
    NIK抑制剂
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