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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2D Structure
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Physico-chemical Properties
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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
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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)
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
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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
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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]