rebastinib   Click here for help

GtoPdb Ligand ID: 9173

Synonyms: DCC 2036 | DCC-2036 | DP-1919
PDB Ligand Immunopharmacology Ligand
Compound class: Synthetic organic
Comment: Rebastinib (DCC-2036) is an investigational orally administered kinase inhibitor, with activity against FLT3-ITD, TIE2, KDR, LYN, BCR-ABL and TRKA kinases. Yes1 inhibition is reported in [6]. This compound has been termed a switch-control inhibitor as it binds to residues Arg386/Glu282 which ABL1 uses to switch between inactive and active conformations [1,3]. Rebastinib inhibits native and phosphphorylated ABL by inducing a type II inactive conformation [1].
It is one of the compounds claimed in patent WO2008046003 [7] and subsequent related patent applications. Rebastinib appears to be Example 1, whilst acknowledging the limitations and complexities applied in compound naming and structure provision in the patent document.
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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

rebastinib is commercially available from our sponsors

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 8
Hydrogen bond donors 3
Rotatable bonds 10
Topological polar surface area 122.54
Molecular weight 553.22
XLogP 4.03
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 CNC(=O)c1nccc(c1)Oc1ccc(c(c1)F)NC(=O)Nc1cc(nn1c1ccc2c(c1)cccn2)C(C)(C)C
Isomeric SMILES CNC(=O)c1nccc(c1)Oc1ccc(c(c1)F)NC(=O)Nc1cc(nn1c1ccc2c(c1)cccn2)C(C)(C)C
InChI InChI=1S/C30H28FN7O3/c1-30(2,3)26-17-27(38(37-26)19-7-9-23-18(14-19)6-5-12-33-23)36-29(40)35-24-10-8-20(15-22(24)31)41-21-11-13-34-25(16-21)28(39)32-4/h5-17H,1-4H3,(H,32,39)(H2,35,36,40)
InChI Key WVXNSAVVKYZVOE-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
IC50 values for rebastinib vs. phosphorylated ABL1 and T315I mutant ABL1 are 4nM and 6nM respectively [1,7]. Rebastinib inhibits BCR-ABL1(T315I)-expressing cell lines, prolongs survival in mouse models of T315I mutant CML and B-lymphoblastic leukemia, and inhibits primary patient leukemia cells expressing T315I in vitro and in vivo [1].
Selectivity at enzymes
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
ABL proto-oncogene 1, non-receptor tyrosine kinase Hs Inhibitor Inhibition 9.1 pIC50 - 1,7
⤷ pIC50 9.1 (IC50 8x10-10 M) [1,7]
YES proto-oncogene 1, Src family tyrosine kinase Hs Inhibitor Inhibition 8.6 – 8.8 pIC50 - 6
⤷ pIC50 8.6 – 8.8 (IC50 2.5x10-9 – 1.5x10-9 M) [6]