NIK SMI1   Click here for help

GtoPdb Ligand ID: 9964

Immunopharmacology Ligand
Compound class: Synthetic organic
Comment: NIK SMI1 is a selective inhibitor of the NF-κB-inducing kinase, NIK (MAP3K14) [1]. NIK is a kinase that operates downstream of several TNF family receptors, including BAFF (TNFRSF13C), TWEAK (TNFRSF12A), CD40 (TNFRSF5), and OX40 (TNFRSF4), and which mediates non-canonical NF-κB signaling. Inhibition of NIK recapitulates the inhibition of BAFF that is observed for example using the anti-BAFF, SLE approved biologic belimumab. The compound has no effect on canonical NF-κB signaling.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 6
Hydrogen bond donors 2
Rotatable bonds 3
Topological polar surface area 105.75
Molecular weight 365.14
XLogP 1.39
No. Lipinski's rules broken 0
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Canonical SMILES COc1cc(nc(c1)c1cccc(c1)C#CC1(O)CCN(C1=O)C)C(=O)N
Isomeric SMILES COc1cc(nc(c1)c1cccc(c1)C#C[C@]1(O)CCN(C1=O)C)C(=O)N
InChI InChI=1S/C20H19N3O4/c1-23-9-8-20(26,19(23)25)7-6-13-4-3-5-14(10-13)16-11-15(27-2)12-17(22-16)18(21)24/h3-5,10-12,26H,8-9H2,1-2H3,(H2,21,24)/t20-/m0/s1
Bioactivity Comments
In a screening panel NIK SMI1 inhibited just 3 off-target kinases, KHS1 (MAP4K5), LRRK2, and PKD1 (PRKD1), by >75% at 1 μM, out of 222 kinases tested. Ki determination established NIK SMI1's selectivity over these off-targets [1].
Selectivity at enzymes
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
mitogen-activated protein kinase kinase kinase 14 Primary target of this compound Hs Inhibitor Inhibition 9.6 pKi - 1
pKi 9.6 (Ki 2.3x10-10 M) [1]
mitogen-activated protein kinase kinase kinase 14 Mm Inhibitor Inhibition 9.4 pKi - 1
pKi 9.4 (Ki 3.95x10-10 M) [1]
mitogen-activated protein kinase kinase kinase kinase 5 Hs Inhibitor Inhibition 7.3 pKi - 1
pKi 7.3 (Ki 4.96x10-8 M) [1]
protein kinase D1 Hs Inhibitor Inhibition 7.1 pKi - 1
pKi 7.1 (Ki 7.52x10-8 M) [1]
leucine rich repeat kinase 2 Hs Inhibitor Inhibition 6.6 pKi - 1
pKi 6.6 (Ki 2.478x10-7 M) [1]