compound 2-2c [PMID: 32003560]   Click here for help

GtoPdb Ligand ID: 10689

PDB Ligand
Compound class: Synthetic organic
Comment: Compound 2-2c is a selective inhibitor of DYRK1A whose chemical structure is derived from that of the DYRK1 kinase inhibitor harmine [1]. It was developed for potential to promote pancreatic β-cell proliferation as a novel mechanism to be applied to the treatment of type 1 diabetes. It produces predicted effects on β-cells in vitro and in vivo.
See also GNF2133, which is a selective DYRK1A inhibitor with a different chemical scaffold [2].
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/). All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 3
Hydrogen bond donors 1
Rotatable bonds 5
Topological polar surface area 70.14
Molecular weight 297.15
XLogP 1.98
No. Lipinski's rules broken 0

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)

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Canonical SMILES COc1ccc2c(c1)n(CCCC(=O)N)c1c2ccnc1C
Isomeric SMILES COc1ccc2c(c1)n(CCCC(=O)N)c1c2ccnc1C
InChI InChI=1S/C17H19N3O2/c1-11-17-14(7-8-19-11)13-6-5-12(22-2)10-15(13)20(17)9-3-4-16(18)21/h5-8,10H,3-4,9H2,1-2H3,(H2,18,21)
InChI Key MRZRJTZGNFPMNY-UHFFFAOYSA-N

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
Bioactivity Comments
Compound has an improved kinase selectivity profile compared to harmine [1] as determined using the DiscoverX KINOMEscan platform. In this screen, in addition to DYRK1A, 10 μM 2-2c strongly inhibited (by >90%) CLK1, CLK2, DYRK1B, DYRK2, HASPIN, HIPK2 and PIK4CB (PI4KB). 2-2c cannot cross the blood-brain-barrier, and in any event has low activity across a range of known harmine off-targets. Harmine is known to inhibit MAO-A, and 2-2c retains this activity (both compounds inhibit MAO-A by ≥95%).
Selectivity at enzymes
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
dual specificity tyrosine phosphorylation regulated kinase 1A Hs Inhibitor Inhibition 7.6 pIC50 - 1
⤷ pIC50 7.6 (IC50 2.5x10-8 M) [1]