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Details

Stereochemistry ACHIRAL
Molecular Formula C29H27F3N6O.ClH
Molecular Weight 569.02
Optical Activity UNSPECIFIED
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of PONATINIB HYDROCHLORIDE

SMILES

Cl.CN1CCN(CC2=CC=C(NC(=O)C3=CC(C#CC4=CN=C5C=CC=NN45)=C(C)C=C3)C=C2C(F)(F)F)CC1

InChI

InChIKey=BWTNNZPNKQIADY-UHFFFAOYSA-N
InChI=1S/C29H27F3N6O.ClH/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);1H

HIDE SMILES / InChI

Molecular Formula C29H27F3N6O
Molecular Weight 532.5595
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Molecular Formula ClH
Molecular Weight 36.461
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Description

Ponatinib (trade name Iclusig, previously AP24534) is developed by ARIAD Pharmaceuticals for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL). Ponatinib has been designed to be effective against these types of tumors. The United States Food and Drug Administration approved the drug as a candidate in 2012, but temporarily suspended sales on 31 October 2013 because of "the risk of life-threatening blood clots and severe narrowing of blood vessels". This suspension was partially lifted on Dec. 20, 2013 with ponatinib being issued revised prescribing information, a new "Black Box Warning" and a "Risk Evaluation and Mitigation Strategy" in place to better evaluate the risks and benefits of using the drug. Ponatinib is an orally bioavailable multitargeted receptor tyrosine kinase (RTK) inhibitor with potential antiangiogenic and antineoplastic activities. Ponatinib inhibits unmutated and all mutated forms of Bcr-Abl, including T315I, the highly drug therapy-resistant missense mutation of Bcr-Abl. This agent also inhibits other tyrosine kinases including those associated with vascular endothelial growth factor receptors (VEGFRs) and fibroblast growth factor receptors (FGFRs); in addition, it inhibits the tyrosine kinase receptor TIE2 and FMS-related tyrosine kinase receptor-3 (Flt3). RTK inhibition by ponatinib may result in the inhibition of cellular proliferation and angiogenesis and may induce cell death. Bcr-Abl is a fusion tyrosine kinase encoded by the Philadelphia chromosome.

CNS Activity

Originator

Approval Year

PubMed

PubMed

TitleDatePubMed
[Therapy of sickle cell anemia by alkalies and magnesium salts. Presentation of a case].
1967 Jun
Discovery of 5-(arenethynyl) hetero-monocyclic derivatives as potent inhibitors of BCR-ABL including the T315I gatekeeper mutant.
2011 Jun 15
The BCR-ABL35INS insertion/truncation mutant is kinase-inactive and does not contribute to tyrosine kinase inhibitor resistance in chronic myeloid leukemia.
2011 Nov 10
Ponatinib is active against imatinib-resistant mutants of FIP1L1-PDGFRA and KIT, and against FGFR1-derived fusion kinases.
2012 Jul
Ponatinib is active against imatinib-resistant mutants of FIP1L1-PDGFRA and KIT, and against FGFR1-derived fusion kinases.
2012 Jul
Ponatinib (AP24534), a multitargeted pan-FGFR inhibitor with activity in multiple FGFR-amplified or mutated cancer models.
2012 Mar
The ins and outs of bcr-abl inhibition.
2012 May
Ponatinib may overcome resistance of FLT3-ITD harbouring additional point mutations, notably the previously refractory F691I mutation.
2012 May
Ponatinib as targeted therapy for FGFR1 fusions associated with the 8p11 myeloproliferative syndrome.
2013 Jan
Ponatinib suppresses the development of myeloid and lymphoid malignancies associated with FGFR1 abnormalities.
2013 Jan
Ponatinib is a potent inhibitor of wild-type and drug-resistant gatekeeper mutant RET kinase.
2013 Sep 5
BET protein antagonist JQ1 is synergistically lethal with FLT3 tyrosine kinase inhibitor (TKI) and overcomes resistance to FLT3-TKI in AML cells expressing FLT-ITD.
2014 Oct
A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease.
2015 Dec
A multi-parameter in vitro screen in human stem cell-derived cardiomyocytes identifies ponatinib-induced structural and functional cardiac toxicity.
2015 Jan
Patents

Sample Use Guides

In Vivo Use Guide
45 mg taken orally once daily with or without food
Route of Administration: Oral
In Vitro Use Guide
Ponatinib inhibited the in vitro tyrosine kinase activity of ABL and T315I mutant ABL with IC50 concentrations of 0.4 and 2.0 nM, respectively. Ponatinib inhibited the in vitro activity of additional kinases with IC50 concentrations between 0.1 and 20 nM, including members of the VEGFR, PDGFR, FGFR, EPH receptors and SRC families of kinases, and KIT, RET, TIE2, and FLT3. Ponatinib inhibited the in vitro viability of cells expressing native or mutant BCR-ABL, including T315I.
Substance Class Chemical
Created
by admin
on Mon Oct 21 20:54:44 UTC 2019
Edited
by admin
on Mon Oct 21 20:54:44 UTC 2019
Record UNII
96R6PU3D8J
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
PONATINIB HYDROCHLORIDE
ORANGE BOOK   USAN   WHO-DD  
USAN  
Official Name English
PONATINIB HYDROCHLORIDE [JAN]
Common Name English
3-(2-(IMIDAZO(1,2-B)PYRIDAZIN-3-YL)ETHYNYL)-4-METHYL-N-(4-((4-METHYLPIPERAZIN-1- YL)METHYL)-3-(TRIFLUOROMETHYL)PHENYL)BENZAMIDE MONOHYDROCHLORIDE
Systematic Name English
BENZAMIDE, 3-(2-IMIDAZO(1,2-B)PYRIDAZIN-3-YLETHYNYL)-4-METHYL-N-(4-((4-METHYL-1- PIPERAZINYL)METHYL)-3-(TRIFLUOROMETHYL)PHENYL)-, HYDROCHLORIDE (1:1)
Systematic Name English
ICLUSIG
Brand Name English
AP24534 HCL
Code English
AP-24534 HCL
Code English
PONATINIB HYDROCHLORIDE [WHO-DD]
Common Name English
PONATINIB HYDROCHLORIDE [ORANGE BOOK]
Common Name English
PONATINIB HYDROCHLORIDE [USAN]
Common Name English
PONATINIB HYDROCHLORIDE [MI]
Common Name English
Classification Tree Code System Code
EU-Orphan Drug EU/3/14/1421
Created by admin on Mon Oct 21 20:54:44 UTC 2019 , Edited by admin on Mon Oct 21 20:54:44 UTC 2019
NCI_THESAURUS C1742
Created by admin on Mon Oct 21 20:54:44 UTC 2019 , Edited by admin on Mon Oct 21 20:54:44 UTC 2019
EMA ASSESSMENT REPORTS ICLUSIG (AUTHORIZED: LEUKEMIA, LYMPHOID)
Created by admin on Mon Oct 21 20:54:44 UTC 2019 , Edited by admin on Mon Oct 21 20:54:44 UTC 2019
NCI_THESAURUS C155700
Created by admin on Mon Oct 21 20:54:44 UTC 2019 , Edited by admin on Mon Oct 21 20:54:44 UTC 2019
Code System Code Type Description
ChEMBL
CHEMBL1171837
Created by admin on Mon Oct 21 20:54:44 UTC 2019 , Edited by admin on Mon Oct 21 20:54:44 UTC 2019
PRIMARY
MERCK INDEX
M11700
Created by admin on Mon Oct 21 20:54:44 UTC 2019 , Edited by admin on Mon Oct 21 20:54:44 UTC 2019
PRIMARY
PUBCHEM
46908927
Created by admin on Mon Oct 21 20:54:44 UTC 2019 , Edited by admin on Mon Oct 21 20:54:44 UTC 2019
PRIMARY
EVMPD
SUB121686
Created by admin on Mon Oct 21 20:54:44 UTC 2019 , Edited by admin on Mon Oct 21 20:54:44 UTC 2019
PRIMARY
CAS
1114544-31-8
Created by admin on Mon Oct 21 20:54:44 UTC 2019 , Edited by admin on Mon Oct 21 20:54:44 UTC 2019
PRIMARY
RXCUI
1364953
Created by admin on Mon Oct 21 20:54:44 UTC 2019 , Edited by admin on Mon Oct 21 20:54:44 UTC 2019
PRIMARY RxNorm
EPA CompTox
1114544-31-8
Created by admin on Mon Oct 21 20:54:44 UTC 2019 , Edited by admin on Mon Oct 21 20:54:44 UTC 2019
PRIMARY
NCI_THESAURUS
C78194
Created by admin on Mon Oct 21 20:54:44 UTC 2019 , Edited by admin on Mon Oct 21 20:54:44 UTC 2019
PRIMARY
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