compound 18 [PMID: 34212719]   Click here for help

GtoPdb Ligand ID: 11595

Compound class: Synthetic organic
Comment: Compound 18 is the most potent of a SAR series of covalent inhibitors of NF-κB-inducing kinase (NIK; MAP3K14) [1]. NIK is a key enzyme in the noncanonical NF-κB pathway. Compound 18 binds irreversibly to Cys444 within the back pocket of the kinase's active site.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 6
Hydrogen bond donors 1
Rotatable bonds 1
Topological polar surface area 94.88
Molecular weight 337.11
XLogP 2.52
No. Lipinski's rules broken 0
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Canonical SMILES C#Cc1ccnc(n1)C#Cc1ccc2c(c1)n(cn2)c1ccnc(n1)N
Isomeric SMILES C#Cc1ccnc(n1)C#Cc1ccc2c(c1)n(cn2)c1ccnc(n1)N
InChI InChI=1S/C19H11N7/c1-2-14-7-9-21-17(24-14)6-4-13-3-5-15-16(11-13)26(12-23-15)18-8-10-22-19(20)25-18/h1,3,5,7-12H,(H2,20,22,25)
Bioactivity Comments
In a screening panel of 40 kinases, 1 μM compound 18 inhibited MLK1, HER4, SGK1, TAK1, PDGFRA, BTK, RIPK2 Aurora B, VEGFR, and SIK2 by >50%, but the uniqueness of Cys444 in NIK is expected to confer high selectivity for the endogenously expressed kinase [1]. Compound 18 inhibits NIK (MAP3K14) activity in vitro, however its antiproliferative activity in tumour cell lines was fairly weak and was likely to offer limited efficacy against cancer cells in situ.
Selectivity at enzymes
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
mitogen-activated protein kinase kinase kinase 14 Hs Inhibitor Irreversible inhibition 6.7 pIC50 - 1
pIC50 6.7 (IC50 2x10-7 M) [1]