repotrectinib   Click here for help

GtoPdb Ligand ID: 10316

Synonyms: Augtyro® | example 93 [US20170334929A1] | TPX-0005 | TPX0005
Approved drug PDB Ligand
repotrectinib is an approved drug (FDA (2023))
Compound class: Synthetic organic
Comment: Repotrectinib (TPX-0005) is a next-generation oral ROS1/NTRK/ALK inhibitor that was rationally designed to overcome tumour resistance due to acquired mutations in these kinases [3-4]. The chemical structure is claimed as example 93 in TP Therapeutics' patent US20170334929A1 [1].
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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 CDK toolkit. 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 5
Hydrogen bond donors 2
Rotatable bonds 0
Topological polar surface area 80.55
Molecular weight 355.14
XLogP 3.08
No. Lipinski's rules broken 0
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.

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Canonical SMILES CC1CNC(=O)c2cnn3c2nc(NC(c2c(O1)ccc(c2)F)C)cc3
Isomeric SMILES C[C@H]1CNC(=O)c2cnn3c2nc(N[C@@H](c2c(O1)ccc(c2)F)C)cc3
InChI InChI=1S/C18H18FN5O2/c1-10-8-20-18(25)14-9-21-24-6-5-16(23-17(14)24)22-11(2)13-7-12(19)3-4-15(13)26-10/h3-7,9-11H,8H2,1-2H3,(H,20,25)(H,22,23)/t10-,11+/m0/s1
InChI Key FIKPXCOQUIZNHB-WDEREUQCSA-N
Bioactivity Comments
In biochemical assays TPX-0005 inhibits wild-type ROS1, TRKA-C, and ALK, as well as JAK2 and several SRC family kinases (including FYN, LYN, YES1, SRC and LCK) [3]. TPX-0005 exhibited potent activity in cellular assays using Ba/F3 cells engineered to express WT or solvent-front mutant ROS, TRK, or ALK. It inhibited ROS1G2032R (IC50 3.3 nM) and ROS1D2033N (IC50 1.3 nM), which are mutants that are resistant to other tyrosine kinase inhibitors, including crizotinib, entrectinib, ceritinib, brigatinib, and ensartinib. Data for inhibition of clinically relevant ALK resistance mutaions is provided in Supplementary Table S4 in [3] (all but one of the IC50s are in the 0.5-5 nM range).
Selectivity at enzymes
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
Janus kinase 2 Hs Inhibitor Inhibition 9.0 pIC50 - 3
⤷ pIC50 9.0 (IC50 1.04x10-9 M) [3]
Selectivity at catalytic receptors
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
c-ros oncogene 1, receptor tyrosine kinase Hs Inhibitor Inhibition 10.1 pIC50 - 3
⤷ pIC50 10.1 (IC50 7x10-11 M) IC50 for ROS1G2032R is 0.5 nM, and for ROS1D2033N is 0.2 nM [3]
neurotrophic receptor tyrosine kinase 3 Hs Inhibitor Inhibition 9.7 pIC50 - 3
⤷ pIC50 9.7 (IC50 2.1x10-10 M) IC50 for TRKCG623R is 4.5 nM. [3]
neurotrophic receptor tyrosine kinase 2 Hs Inhibitor Inhibition 9.5 pIC50 - 3
⤷ pIC50 9.5 (IC50 3x10-10 M) IC50 for TRKBG639R is 2.7 nM [3]
neurotrophic receptor tyrosine kinase 1 Hs Inhibitor Inhibition 9.3 pIC50 - 3
⤷ pIC50 9.3 (IC50 5.3x10-10 M) IC50 for TRKAG595R is 2.7 nM [3]
ALK receptor tyrosine kinase Hs Inhibitor Inhibition 9.0 pIC50 - 3
⤷ pIC50 9.0 (IC50 1.04x10-9 M) IC50 for ALKG1202R is 1.2 nM. [3]