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CIRc-014   Click here for help

GtoPdb Ligand ID: 14493

Synonyms: compound 33 [PMID: 41721763]
Compound class: Synthetic organic
Comment: This is an orally bioavailable macrocyclic peptide that is reported to bind the RxL motif within the conserved hydrophobic patch on the surface of cyclin A and B proteins, to effectively inhibit the protein-protein interactions between the cyclins and their cognate cyclin-dependent kinases (CDKs) and block CDK-mediated cell cycle regulatory signalling [1-2]. Disrupting cyclin A mediates de-repression of E2F transcription factor activity, and which in turn induces E2F hyperactivation and apoptisis. This mechanism is proposed to disrupt cell cycle progression in cancer cells with E2F dysfunction (identified as a potential synthetic lethal vulnerability), resulting in apoptosis and tumour regression.
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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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View interactive charts of activity data across species
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 14
Hydrogen bond donors 2
Rotatable bonds 16
Topological polar surface area 161.03
Molecular weight 962.46
XLogP 6.26
No. Lipinski's rules broken 4

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 CC(C)C[C@H]1C(=O)N(C)[C@@H](CC2=C(N=CC(=C2)Cl)OC3CC3)C(=O)N(C)CCCCCCC[C@@H](C(=O)N1)N(C)C(=O)[C@H](C4CC4)NC(=O)[C@@H]5C[C@H](CN5C(=O)C6(CC(C6)(F)F)C(F)(F)F)F
Isomeric SMILES CC(C)C[C@@H]1NC(=O)[C@H](CCCCCCCN(C)C(=O)[C@H](CC2=C(OC3CC3)N=CC(Cl)=C2)N(C)C1=O)N(C)C(=O)[C@@H](NC(=O)[C@@H]4C[C@@H](F)CN4C(=O)C5(CC(F)(F)C5)C(F)(F)F)C6CC6
InChI InChI=1S/C45H62ClF6N7O7/c1-25(2)17-31-39(62)58(5)34(19-27-18-28(46)21-53-38(27)66-30-14-15-30)40(63)56(3)16-10-8-6-7-9-11-32(36(60)54-31)57(4)41(64)35(26-12-13-26)55-37(61)33-20-29(47)22-59(33)42(65)43(45(50,51)52)23-44(48,49)24-43/h18,21,25-26,29-35H,6-17,19-20,22-24H2,1-5H3,(H,54,60)(H,55,61)/t29-,31+,32+,33+,34+,35+/m1/s1
InChI Key PTZDPNNZZODMBT-FIIVPKDJSA-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
Oral administration of compound 33 induces tumour regression in xenograft models of small cell lung cancer [1].
Selectivity at other protein targets
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
cyclin B1 Hs Inhibitor Binding >7.7 pIC50 - 1
⤷ pIC50 >7.7 (IC50 <2x10-8 M) [1]
Description: Binding affinity for CDK1/Cyclin B1 complex, determined by fluorescence polarization
cyclin A1 Hs Inhibitor Binding 7.3 pIC50 - 1
⤷ pIC50 7.3 (IC50 5x10-8 M) [1]
Description: Binding affinity for CDK2/Cyclin A1 complex, determined by fluorescence polarization