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tarloxotinib   Click here for help

GtoPdb Ligand ID: 9409

Synonyms: PR610 | tarloxotinib cation | TH-4000
Compound class: Synthetic organic
Comment: Tarloxotinib (TH-4000) is a hypoxia-activated prodrug (HAP) [1] being developed by Threshold Pharmaceuticals. Delivered as the bromide salt (PubChem CID 51038315) as described in its INN record. The compound undergoes activation selectively within the hypoxic tumour compartment to produce an irreversible pan-ErbB tyrosine-kinase inhibitor, represented by TH-4000E [1]. The 4-nitroimidazole trigger on the tertiary amine side chain facilitates activation. This is one of the first molecularly targeted HAPs to be developed.
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 7
Hydrogen bond donors 2
Rotatable bonds 10
Topological polar surface area 140.76
Molecular weight 600.09
XLogP 3.45
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 O=C(Nc1ncc2c(c1)c(ncn2)Nc1ccc(c(c1)Br)Cl)C=CC[N+](Cc1n(C)cnc1[N+](=O)[O-])(C)C
Isomeric SMILES O=C(Nc1ncc2c(c1)c(ncn2)Nc1ccc(c(c1)Br)Cl)/C=C/C[N+](Cc1n(C)cnc1[N+](=O)[O-])(C)C
InChI InChI=1S/C24H23BrClN9O3/c1-33-14-30-24(34(37)38)20(33)12-35(2,3)8-4-5-22(36)32-21-10-16-19(11-27-21)28-13-29-23(16)31-15-6-7-18(26)17(25)9-15/h4-7,9-11,13-14H,8,12H2,1-3H3,(H-,27,28,29,31,32,36)/p+1/b5-4+
InChI Key MUJMYVFVAWFUJL-SNAWJCMRSA-O

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
To date (Nov 2016) data for this drug has been published in abstract form only (Abstract 5358: The hypoxia-activated EGFR-TKI TH-4000 overcomes erlotinib-resistance in preclinical NSCLC models at plasma levels achieved in a Phase 1 clinical trial and Abstract e13548: TH-4000, a hypoxia-activated EGFR/Her2 inhibitor to treat EGFR-TKI resistant T790M-negative NSCLC. We await publication in a peer reviewed article.
Selectivity at catalytic receptors
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
epidermal growth factor receptor Hs Inhibitor Inhibition - - - 1
⤷ [1]