PONATINIB

Details

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

SHOW SMILES / InChI

Structure Search

SMILES

CN1CCN(CC2=C(C=C(NC(=O)C3=CC=C(C)C(=C3)C#CC4=CN=C5C=CC=NN45)C=C2)C(F)(F)F)CC1

InChI

InChIKey=PHXJVRSECIGDHY-UHFFFAOYSA-N

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)

HIDE SMILES / InChI

Molecular Formula	C29H27F3N6O
Molecular Weight	532.5595
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf

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

Targets

Primary Target	Pharmacology	Condition	Potency
Calcium/calmodulin-dependent protein kinase type II subunit alpha 2 Target ID: 12345.0 Gene ID: 25400.0 Gene Symbol: Camk2a Target Organism: Rattus norvegicus (Rat) Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/203469s023lbl.pdf	Inhibitor 8504
Phospholipase A2 9 Target ID: P00594 Gene ID: NA Gene Symbol: PLA2G1B Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/203469s023lbl.pdf	Inhibitor 8504		0.4 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Chronic myeloid leukemia 24 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf	Primary	Approved 8583	Iclusig Approved Use To treat adults with chronic myeloid leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL), two rare blood and bone marrow diseases. Launch Date 2020
Headache 47 Sources: https://pubmed.ncbi.nlm.nih.gov/1373760	Palliative	Discontinued	Launch Date 1970
Philadelphia chromosome positive acute lymphoblastic leukemia 7 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf	Inactive Ingredient	Approved 8583	Approved Use To treat adults with chronic myeloid leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph ALL), two rare blood and bone marrow diseases. Launch Date 2013

C_max

Value	Dose	Analyte	Population
183.1 nM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/23190221	60 mg 1 times / day steady-state, oral dose: 60 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	PONATINIB blood	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
73 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf	45 mg 1 times / day steady-state, oral dose: 45 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	PONATINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
73 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf	45 mg 1 times / day steady-state, oral dose: 45 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	PONATINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
2856 nM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/23190221	60 mg 1 times / day steady-state, oral dose: 60 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	PONATINIB blood	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1253 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf	45 mg 1 times / day steady-state, oral dose: 45 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	PONATINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1253 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf	45 mg 1 times / day steady-state, oral dose: 45 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	PONATINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
19.7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/23190221	60 mg 1 times / day steady-state, oral dose: 60 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		PONATINIB blood	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
24 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf	45 mg 1 times / day steady-state, oral dose: 45 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		PONATINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
1% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf	45 mg 1 times / day steady-state, oral dose: 45 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		PONATINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf	45 mg 1 times / day steady-state, oral dose: 45 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		PONATINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
60 mg 1 times / day multiple, oral MTD Dose: 60 mg, 1 times / day Route: oral Route: multiple Dose: 60 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/23190221	unhealthy Health Status: unhealthy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/23190221	DLT: Lipase increased, Blood amylase increased... Dose limiting toxicities: Lipase increased (grade 3-4, 4 patients) Blood amylase increased (grade 3-4, 4 patients) Fatigue (grade 3, 1 patient) Alanine aminotransferase increased (grade 3, 1 patient) Aspartate aminotransferase increased (grade 3, 1 patient) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/23190221
45 mg 1 times / day steady, oral Recommended Dose: 45 mg, 1 times / day Route: oral Route: steady Dose: 45 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf	unhealthy Health Status: unhealthy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf	Disc. AE: Neutropenia, Thrombocytopenia... AEs leading to discontinuation/dose reduction: Neutropenia (13%) Thrombocytopenia (12%) Rash (11%) Abdominal pain (11%) Pancreatitis (6%) ALT increased (6%) AST increased (6%) GGT increased (6%) Myocardial ischemia (serious, 5%) Arterial thrombosis (serious, 34 patients) Ischemia cerebral (serious, 8 patients) Peripheral arterial ischemia (serious, 7 patients) Arterial stenosis (serious, 5%) Myocardial infarction (serious, 14 patients) Cerebrovascular event (serious, 2%) Extremity necrosis (serious, 3 patients) Infection (1%) Thrombocytopenia (30%) Thrombocytopenia (4%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf
60 mg 1 times / day multiple, oral Recommended\|MTD Dose: 60 mg, 1 times / day Route: oral Route: multiple Dose: 60 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf	unhealthy Health Status: unhealthy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf	Disc. AE: Ischemia... AEs leading to discontinuation/dose reduction: Ischemia (serious, 4 patients) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf

AEs

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:78543	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:78543
ChemicalBook	CB12518324	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB12518324
eMolecules	32176636	https://www.emolecules.com/cgi-bin/more?vid=32176636
MolPort	MolPort-009-679-483	https://www.molport.com/shop/molecule-link/MolPort-009-679-483
Selleck Chemicals	AP24534	http://www.selleckchem.com/products/AP24534.html
ZINC	ZINC000036701290	http://zinc15.docking.org/substances/ZINC000036701290

PubMed

Title	Date	PubMed
A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease.	2015-12	26502155
A multi-parameter in vitro screen in human stem cell-derived cardiomyocytes identifies ponatinib-induced structural and functional cardiac toxicity.	2015-01	25304212
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.	2014-10	25053825
Ponatinib is a potent inhibitor of wild-type and drug-resistant gatekeeper mutant RET kinase.	2013-09-05	23811235
Ponatinib as targeted therapy for FGFR1 fusions associated with the 8p11 myeloproliferative syndrome.	2013-01	22875613
Ponatinib suppresses the development of myeloid and lymphoid malignancies associated with FGFR1 abnormalities.	2013-01	22781593
Ponatinib as targeted therapy for FGFR1 fusions associated with the 8p11 myeloproliferative syndrome.	2013-01	22875613
Ponatinib suppresses the development of myeloid and lymphoid malignancies associated with FGFR1 abnormalities.	2013-01	22781593
Ponatinib is active against imatinib-resistant mutants of FIP1L1-PDGFRA and KIT, and against FGFR1-derived fusion kinases.	2012-07	22301675
Ponatinib is active against imatinib-resistant mutants of FIP1L1-PDGFRA and KIT, and against FGFR1-derived fusion kinases.	2012-07	22301675
Ponatinib may overcome resistance of FLT3-ITD harbouring additional point mutations, notably the previously refractory F691I mutation.	2012-05	22409268
The ins and outs of bcr-abl inhibition.	2012-05	23226582
Ponatinib may overcome resistance of FLT3-ITD harbouring additional point mutations, notably the previously refractory F691I mutation.	2012-05	22409268
Ponatinib (AP24534), a multitargeted pan-FGFR inhibitor with activity in multiple FGFR-amplified or mutated cancer models.	2012-03	22238366
The BCR-ABL35INS insertion/truncation mutant is kinase-inactive and does not contribute to tyrosine kinase inhibitor resistance in chronic myeloid leukemia.	2011-11-10	21908430
The BCR-ABL35INS insertion/truncation mutant is kinase-inactive and does not contribute to tyrosine kinase inhibitor resistance in chronic myeloid leukemia.	2011-11-10	21908430
Discovery of 5-(arenethynyl) hetero-monocyclic derivatives as potent inhibitors of BCR-ABL including the T315I gatekeeper mutant.	2011-06-15	21561767
Discovery of 5-(arenethynyl) hetero-monocyclic derivatives as potent inhibitors of BCR-ABL including the T315I gatekeeper mutant.	2011-06-15	21561767
Potent activity of ponatinib (AP24534) in models of FLT3-driven acute myeloid leukemia and other hematologic malignancies.	2011-06	21482694
Structural mechanism of the Pan-BCR-ABL inhibitor ponatinib (AP24534): lessons for overcoming kinase inhibitor resistance.	2011-01	21118377
Discovery of 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-abelson (BCR-ABL) kinase including the T315I gatekeeper mutant.	2010-06-24	20513156
AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance.	2009-11-06	19878872
Inhibitors of ABL and the ABL-T315I mutation.	2008	18673174
Infectious influenza A and B virus variants with long carboxyl terminal deletions in the NS1 polypeptides.	1987-02	3811235
[Therapy of sickle cell anemia by alkalies and magnesium salts. Presentation of a case].	1967-06	5304212

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 Mar 31 19:22:10 GMT 2025` Edited by `admin` on `Mon Mar 31 19:22:10 GMT 2025`
Record UNII	4340891KFS
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

PONATINIB

Official Name

English

ponatinib [INN]

Preferred Name

English

PONATINIB [VANDF]

Common Name

English

Ponatinib [WHO-DD]

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

Systematic Name

English

PONATINIB [MI]

Common Name

English

AP24534

Code

English

AP-24534

Code

English

BENZAMIDE, 3-(2-IMIDAZO(1,2-B)PYRIDAZIN-3-YLETHYNYL)-4-METHYL-N-(4-((4-METHYL-1- PIPERAZINYL)METHYL)-3-(TRIFLUOROMETHYL)PHENYL)-

Systematic Name

English

PONATINIB [USAN]

Common Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

466714