compound 11 [PMID: 26431428]   Click here for help

GtoPdb Ligand ID: 9989

PDB Ligand
Compound class: Synthetic organic
Comment: Compound 11 is a potent, selective, and brain penetrant inhibitor of dual leucine zipper kinase (DLK, MAP3K12) [2]. DLK inhibitors are being investigated for neuroprotective potential.
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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 5
Topological polar surface area 79
Molecular weight 392.23
XLogP 2.52
No. Lipinski's rules broken 0
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Canonical SMILES N#Cc1ccnc(c1)Nc1cc(n(n1)C1CCCC1)C1CCN(CC1)C1COC1
Isomeric SMILES N#Cc1ccnc(c1)Nc1cc(n(n1)C1CCCC1)C1CCN(CC1)C1COC1
InChI InChI=1S/C22H28N6O/c23-13-16-5-8-24-21(11-16)25-22-12-20(28(26-22)18-3-1-2-4-18)17-6-9-27(10-7-17)19-14-29-15-19/h5,8,11-12,17-19H,1-4,6-7,9-10,14-15H2,(H,24,25,26)
Bioactivity Comments
Compound 11 is active in an in vivo nerve injury model [2]. It inhibits JNK phosphorylation downstream of DLK signalling with an IC50 of 536 nM. Compound 11 was screened for DLK selectivity against a selected panel of 58 kinases. Those with >50% inhibition were CSF1R, Flt3, GSK3β, Kit, Src, TrkA and TrkB (see Figure 6 in [2]), but all calculated IC50 values were in the micromolar range or above. It is selective for DLK over the three JNKs (IC50s 1-5 μM) and over the three related mixed lineage kinases MLK1, MLK2 and MLK3 (IC50s all >10 μM).
Selectivity at enzymes
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
mitogen-activated protein kinase kinase kinase 12 Primary target of this compound Hs Inhibitor Inhibition 7.4 pKi - 2
pKi 7.4 (Ki 4.2x10-8 M) [2]
mitogen-activated protein kinase 8 Hs Inhibitor Inhibition 6.0 pIC50 - 2
pIC50 6.0 (IC50 1.004x10-6 M) [2]
mitogen-activated protein kinase 10 Hs Inhibitor Inhibition 5.7 pIC50 - 2
pIC50 5.7 (IC50 2.1x10-6 M) [2]
mitogen-activated protein kinase kinase 4 Hs Inhibitor Inhibition <5.3 pIC50 - 1
pIC50 <5.3 (IC50 >5x10-6 M) [1]
mitogen-activated protein kinase kinase 7 Hs Inhibitor Inhibition 5.3 pIC50 - 2
pIC50 5.3 (IC50 5x10-6 M) [2]