PQR620   Click here for help

GtoPdb Ligand ID: 10142

Synonyms: compound 3 [PMID: 30359003] | PQR-620
Compound class: Synthetic organic
Comment: PQR620 is a potent and selective inhibitor of mTORC1/2 mTOR-containing complexes that was developed by PIQUR Therapeutics [2]. It is brain-penetrating and is being analysed for clinical potential in neurological disorders and cancer. PQR620 was designed as a more effective alternative to the rapalogs sirolimus, everolimus and temsirolimus which show only modest overall response rates in solid tumours [1]. Chemically PQR620 is a rationally designed derivative of bimiralisib (PQR309), in which bimiralisib's trifluoromethyl group is substituted by a difluoromethyl group, and its morpholino groups are substituted with oxo-azabicyclo moieties.
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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 9
Hydrogen bond donors 1
Rotatable bonds 4
Topological polar surface area 102.52
Molecular weight 445.2
XLogP 2.66
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 Nc1ncc(c(c1)C(F)F)c1nc(nc(n1)N1C2COCC1CC2)N1C2COCC1CC2
Isomeric SMILES Nc1ncc(c(c1)C(F)F)c1nc(nc(n1)N1C2COCC1CC2)N1C2COCC1CC2
InChI InChI=1S/C21H25F2N7O2/c22-18(23)15-5-17(24)25-6-16(15)19-26-20(29-11-1-2-12(29)8-31-7-11)28-21(27-19)30-13-3-4-14(30)10-32-9-13/h5-6,11-14,18H,1-4,7-10H2,(H2,24,25)
InChI Key UGDKPWVVBKHRDK-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
PQR620 exhibits favourable selectivity for mTOR over PI3K and other protein kinases [2]. It prevents proliferation in a screening panel of 66 cancer cell lines, and is anti-proliferative in a mouse xenograft model of ovarian cancer. Brain exposure is evidenced by PQR620's ability to reduce epileptic seizures in a tuberous sclerosis complex (TSC) mouse model.
Selectivity at enzymes
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
mechanistic target of rapamycin kinase Primary target of this compound Hs Inhibitor Inhibition 9.6 pKd - 2
⤷ pKd 9.6 (Kd 2.7x10-10 M) [2]
Description: Binding affinity constant.
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha Hs Inhibitor Inhibition 6.0 pKd - 2
⤷ pKd 6.0 (Kd 1x10-6 M) [2]
phosphatidylinositol 3-kinase catalytic subunit type 3 Hs Inhibitor Inhibition 5.6 pKd - 2
⤷ pKd 5.6 (Kd 2.75x10-6 M) [2]
mechanistic target of rapamycin kinase Hs Inhibitor Inhibition 8.0 pKi - 2
⤷ pKi 8.0 (Ki 1.08x10-8 M) [2]
Description: In vitro inhibition constant.
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha Hs Inhibitor Inhibition 5.4 pKi - 2
⤷ pKi 5.4 (Ki 4.203x10-6 M) [2]