ponatinib   Click here for help

GtoPdb Ligand ID: 5890

Synonyms: AP24534 | Iclusig®
Approved drug PDB Ligand Immunopharmacology Ligand
ponatinib is an approved drug (FDA (2012), EMA (2013))
Compound class: Synthetic organic
Comment: Ponatinib is a Type-1 kinase inhibitor. It is a third generation BCR-Abl inhibitor. Use of ponatinib is subject to additional monitoring due to the observed serious risk of liver problems or blood clots (including heart attack and stroke, collectively referred to as arterial occlusive events, or AOEs). Final 5-year results of safety and efficacy in Ph+ leukemia as evaluated in NCT01207440 are reported by Cortes et al. (2018) [1].
Marketed formulations contain ponatinib hydrochloride (PubChem CID 46908927).
Ponatinib has also been reported as a dual inhibitor of RIPK1 and RIPK3 which inhibits experimental models of RIPK1- and RIPK3-dependent cell death (necroptosis) [5]. On the basis of these findings, hybrid ponatinib/necrostatin-1 (a RIPK1 and IDO inhibitor) were designed and tested for potential to target RIPK1- and RIPK3-driven inflammatory pathologies.
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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

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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 6
Hydrogen bond donors 1
Rotatable bonds 6
Topological polar surface area 65.77
Molecular weight 532.22
XLogP 5.2
No. Lipinski's rules broken 1
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 CN1CCN(CC1)Cc1ccc(cc1C(F)(F)F)NC(=O)c1ccc(c(c1)C#Cc1cnc2n1nccc2)C
Isomeric SMILES CN1CCN(CC1)Cc1ccc(cc1C(F)(F)F)NC(=O)c1ccc(c(c1)C#Cc1cnc2n1nccc2)C
InChI InChI=1S/C29H27F3N6O/c1-20-5-6-22(16-21(20)8-10-25-18-33-27-4-3-11-34-38(25)27)28(39)35-24-9-7-23(26(17-24)29(30,31)32)19-37-14-12-36(2)13-15-37/h3-7,9,11,16-18H,12-15,19H2,1-2H3,(H,35,39)
InChI Key PHXJVRSECIGDHY-UHFFFAOYSA-N
Bioactivity Comments
Comparison of target residency time (τ) and biochemical IC50 values for ponatinib vs. 10 kinases reveals an alternative selectivity profile. Among the kinases inhibited with similar potency to ABL, wide differences in τ were detected: TIE2 6 min, DDR2, FGFR1, FYN and SRC ~2-3 hours, ABL 180 hours [6].
Selectivity at enzymes
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
cyclin dependent kinase 8 Hs Inhibitor Inhibition 8.2 pKd - 2
⤷ pKd 8.2 (Kd 6.77x10-9 M) [2]
Description: CDK8/cyclin C.
cyclin dependent kinase 19 Hs Inhibitor Inhibition 7.9 pKd - 2
⤷ pKd 7.9 (Kd 1.19x10-8 M) [2]
Description: CDK19/cyclin C.
receptor interacting serine/threonine kinase 3 Hs Inhibitor Inhibition 8.8 pKi - 5
⤷ pKi 8.8 (Ki 1.6x10-9 M) [5]
Description: Inhibition of recombinant RIPK3 in an in vitro ADP-Glo assay (Promega).
ABL proto-oncogene 1, non-receptor tyrosine kinase Primary target of this compound Hs Inhibitor Inhibition 8.1 pIC50 - 3
⤷ pIC50 8.1 (IC50 8.6x10-9 M) [3]
receptor interacting serine/threonine kinase 1 Hs Inhibitor Inhibition 7.9 pIC50 - 5
⤷ pIC50 7.9 (IC50 1.2x10-8 M) [5]
Description: Inhibition of recombinant RIPK1 in an in vitro ADP-Glo assay (Promega).
receptor interacting serine/threonine kinase 2 Hs Inhibitor Inhibition 7.8 pIC50 - 5
⤷ pIC50 7.8 (IC50 1.4x10-8 M) [5]
Description: Inhibition of recombinant RIPK2 in an in vitro ADP-Glo assay (Promega).
Selectivity at catalytic receptors
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
ret proto-oncogene Hs Inhibitor Inhibition 8.2 pIC50 - 4
⤷ pIC50 8.2 (IC50 7x10-9 M) [4]