kinase inhibitor 2 [PMID: 30199702]   Click here for help

GtoPdb Ligand ID: 10081

Compound class: Synthetic organic
Comment: This compound is reported by Compain et al. (2018) as the protein kinase inhibitor component of a β-glucuronidase-responsive albumin-binding prodrug that was designed as a novel cancer therapeutic [1]. The biological activity of inhibitor 2 is blocked when it is incoprorated in the enzyme-responsive prodrug. The active inhibitor is released only in the presence of β-glucuronidase (e.g. as exists in the tumour microenvironment), so should faciliate selective delivery of the drug to the tumour whilst minimising systemic off-target and adverse effects. Compound 2 is a multi-kinase inhibitor with a similar selectivity profile as seliciclib, but with additional potent inhibitory activity at DYRK3 and GSK3.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 7
Hydrogen bond donors 3
Rotatable bonds 7
Topological polar surface area 106.05
Molecular weight 456.27
XLogP 4.61
No. Lipinski's rules broken 0
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Canonical SMILES NC1CCC(CC1)Nc1nc(NCc2ccc(cc2)c2ccccn2)n2c(n1)c(cn2)C(C)C
Isomeric SMILES N[C@@H]1CC[C@H](CC1)Nc1nc(NCc2ccc(cc2)c2ccccn2)n2c(n1)c(cn2)C(C)C
InChI InChI=1S/C26H32N8/c1-17(2)22-16-30-34-24(22)32-25(31-21-12-10-20(27)11-13-21)33-26(34)29-15-18-6-8-19(9-7-18)23-5-3-4-14-28-23/h3-9,14,16-17,20-21H,10-13,15,27H2,1-2H3,(H2,29,31,32,33)/t20-,21-
Bioactivity Comments
Inhibitor 2 exhibits low nanomolar antiproliferative activity against a range of cancer cell lines in vitro [1]. When incorporated in to the prodrug structure the inhibitor is inactive in vitro in the absence of β-glucuronidase (IC50 > 200 nM vs. A549 human lung carcinoma cells), but is fully active when β-glucuronidase is added to the culture medium (IC50 10.3 nM).
Selectivity at enzymes
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
cyclin dependent kinase 9 Hs Inhibitor Inhibition 7.3 pIC50 - 1
pIC50 7.3 (IC50 4.9x10-8 M) [1]
Description: CDK9/cyclin T
cyclin dependent kinase 5 Hs Inhibitor Inhibition 7.3 pIC50 - 1
pIC50 7.3 (IC50 5x10-8 M) [1]
Description: CDK5/p25
cyclin dependent kinase 2 Hs Inhibitor Inhibition 7.2 pIC50 - 1
pIC50 7.2 (IC50 6.8x10-8 M) [1]
Description: CDK2/cyclin A
cyclin dependent kinase 1 Hs Inhibitor Inhibition 7.2 pIC50 - 1
pIC50 7.2 (IC50 7x10-8 M) [1]
Description: CDK1/cyclin B
CDC like kinase 4 Hs Inhibitor Inhibition 7.1 pIC50 - 1
pIC50 7.1 (IC50 8.9x10-8 M) [1]
dual specificity tyrosine phosphorylation regulated kinase 3 Hs Inhibitor Inhibition 6.4 pIC50 - 1
pIC50 6.4 (IC50 3.8x10-7 M) [1]