U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ACHIRAL
Molecular Formula C29H27F3N6O.ClH
Molecular Weight 569.02
Optical Activity NONE
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(C)C(=C3)C#CC4=CN=C5C=CC=NN45)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

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

CNS Active
3913

Originator

ARIAD
5

Approval Year

2012
595
Targets

Targets

Primary TargetPharmacologyConditionPotency
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)
Inhibitor
8297
Phospholipase A2
9
Target ID: P00594
Gene ID: NA
Gene Symbol: PLA2G1B
Inhibitor
8297
 0.4 nM [IC50]
mitochondrion inheritance
2
Target ID: GO:0000001
Target Organism: Homo sapiens (Human)
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Approved
8429
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
Palliative
Discontinued

Launch Date

1970
Inactive Ingredient
Approved
8429

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
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
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
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: 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 unknown
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
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
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: 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 unknown
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
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
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: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
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 unknown
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
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
n = 449
Health Status: unhealthy
Population Size: 449
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf
Disc. AE: Infection, Thrombocytopenia...
AEs leading to
discontinuation/dose reduction:
Infection (1%)
Thrombocytopenia (30%)
Neutropenia (13%)
Lipase increased (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)
Thrombocytopenia (4%)
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf
60 mg 1 times / day multiple, oral
Recommended,MTD,Overdose
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
n = 19
Health Status: unhealthy
Population Size: 19
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
60 mg 1 times / day multiple, oral
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
n = 19
Health Status: unhealthy
Population Size: 19
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000MedR.pdf
https://pubmed.ncbi.nlm.nih.gov/23190221
DLT: Blood amylase increased, Fatigue...
Dose limiting toxicities:
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)
Lipase increased (grade 3-4, 4 patients)
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000MedR.pdf
https://pubmed.ncbi.nlm.nih.gov/23190221
AEs

AEs

AESignificanceDosePopulation
Infection 1%
Disc. AE
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
n = 449
Health Status: unhealthy
Population Size: 449
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf
Abdominal pain 11%
Disc. AE
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
n = 449
Health Status: unhealthy
Population Size: 449
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf
Rash 11%
Disc. AE
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
n = 449
Health Status: unhealthy
Population Size: 449
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf
Lipase increased 12%
Disc. AE
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
n = 449
Health Status: unhealthy
Population Size: 449
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf
Neutropenia 13%
Disc. AE
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
n = 449
Health Status: unhealthy
Population Size: 449
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf
Thrombocytopenia 30%
Disc. AE
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
n = 449
Health Status: unhealthy
Population Size: 449
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf
Thrombocytopenia 4%
Disc. AE
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
n = 449
Health Status: unhealthy
Population Size: 449
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf
ALT increased 6%
Disc. AE
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
n = 449
Health Status: unhealthy
Population Size: 449
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf
AST increased 6%
Disc. AE
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
n = 449
Health Status: unhealthy
Population Size: 449
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf
GGT increased 6%
Disc. AE
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
n = 449
Health Status: unhealthy
Population Size: 449
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf
Pancreatitis 6%
Disc. AE
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
n = 449
Health Status: unhealthy
Population Size: 449
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf
Myocardial infarction serious, 14 patients
Disc. AE
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
n = 449
Health Status: unhealthy
Population Size: 449
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf
Cerebrovascular event serious, 2%
Disc. AE
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
n = 449
Health Status: unhealthy
Population Size: 449
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf
Extremity necrosis serious, 3 patients
Disc. AE
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
n = 449
Health Status: unhealthy
Population Size: 449
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf
Arterial thrombosis serious, 34 patients
Disc. AE
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
n = 449
Health Status: unhealthy
Population Size: 449
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf
Arterial stenosis serious, 5%
Disc. AE
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
n = 449
Health Status: unhealthy
Population Size: 449
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf
Myocardial ischemia serious, 5%
Disc. AE
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
n = 449
Health Status: unhealthy
Population Size: 449
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf
Peripheral arterial ischemia serious, 7 patients
Disc. AE
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
n = 449
Health Status: unhealthy
Population Size: 449
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf
Ischemia cerebral serious, 8 patients
Disc. AE
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
n = 449
Health Status: unhealthy
Population Size: 449
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf
Ischemia serious, 4 patients
Disc. AE
60 mg 1 times / day multiple, oral
Recommended,MTD,Overdose
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
n = 19
Health Status: unhealthy
Population Size: 19
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf
Alanine aminotransferase increased grade 3, 1 patient
DLT
60 mg 1 times / day multiple, oral
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
n = 19
Health Status: unhealthy
Population Size: 19
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000MedR.pdf
https://pubmed.ncbi.nlm.nih.gov/23190221
Aspartate aminotransferase increased grade 3, 1 patient
DLT
60 mg 1 times / day multiple, oral
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
n = 19
Health Status: unhealthy
Population Size: 19
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000MedR.pdf
https://pubmed.ncbi.nlm.nih.gov/23190221
Fatigue grade 3, 1 patient
DLT
60 mg 1 times / day multiple, oral
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
n = 19
Health Status: unhealthy
Population Size: 19
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000MedR.pdf
https://pubmed.ncbi.nlm.nih.gov/23190221
Blood amylase increased grade 3-4, 4 patients
DLT
60 mg 1 times / day multiple, oral
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
n = 19
Health Status: unhealthy
Population Size: 19
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000MedR.pdf
https://pubmed.ncbi.nlm.nih.gov/23190221
Lipase increased grade 3-4, 4 patients
DLT
60 mg 1 times / day multiple, oral
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
n = 19
Health Status: unhealthy
Population Size: 19
Sources:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000MedR.pdf
https://pubmed.ncbi.nlm.nih.gov/23190221
Overview

Overview

CYP3A4CYP2C9CYP2D6hERG
substrate
1737

inducer
781
inhibitor
1767
substrate
1217

inhibitor
1852
inhibitor
1612

OverviewOther

Other InhibitorOther SubstrateOther Inducer
CYP1A2
1524

CYP2B6
810

CYP2C8
911

CYP2C19
1478

CYP3A
214

P-gp
1461

BCRP
699

OATP1B1
788

OATP1B3
706

OCT1
512

OCT2
647

OAT1
599

OAT3
642

BSEP
402

CYP3A4
2
CYP2C8
693

CYP3A5
395

P-gp
1537

BCRP
561

OATP1B1
406

OATP1B3
350

OCT1
327
Drug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
CYP3A4
1925
test
2
CYP2C9
1819
 little [IC50 10.8 uM]
CYP2D6
1891
 little [IC50 11.6 uM]
CYP1A2
1692
 little [IC50 13.3 uM]
CYP2C19
1553
 little [IC50 5.2 uM]
CYP2B6
1001
 little [IC50 5.6 uM]
CYP2C8
965
 little [IC50 6.1 uM]
CYP3A
298
 little [IC50 8.3 uM]
OAT1
603
 no
OAT3
644
 no
OATP1B1
803
 no
OATP1B3
715
 no
OCT1
543
 no
OCT2
648
 no
CYP3A4
1925
 yes [Activation 0.6 uM]
BCRP
773
 yes [IC50 0.013 uM]
P-gp
1650
 yes [IC50 0.49 uM]
BSEP
403
 yes [IC50 32 uM]
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
CYP3A4
1737
 major
yes (co-administration study)
Comment: ketoconazole increased cmax of ponatinib by 47%, auc by 78%
CYP2C8
693
 minor
CYP2D6
1217
 minor
CYP3A5
395
 minor
OATP1B1
406
 no
OATP1B3
350
 no
OCT1
327
 no
BCRP
561
 weak
P-gp
1537
 weak
Tox targets

Tox targets

TargetModalityActivityMetaboliteClinical evidence
hERG
1647
Sourcing

Sourcing

Vendor/AggregatorIDURL
ChEBI
CHEBI:78543
https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:78543
ChemicalBook
CB12518324
https://www.chemicalbook.com/ChemicalProductProperty_EN_CB12518324
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
eMolecules
32176636
https://www.emolecules.com/cgi-bin/more?vid=32176636
PubMed

PubMed

TitleDatePubMed
Infectious influenza A and B virus variants with long carboxyl terminal deletions in the NS1 polypeptides.
1987 Feb
Inhibitors of ABL and the ABL-T315I mutation.
2008
AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance.
2009 Nov 6
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 Jun 24
Structural mechanism of the Pan-BCR-ABL inhibitor ponatinib (AP24534): lessons for overcoming kinase inhibitor resistance.
2011 Jan
Discovery of 5-(arenethynyl) hetero-monocyclic derivatives as potent inhibitors of BCR-ABL including the T315I gatekeeper mutant.
2011 Jun 15
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
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 may overcome resistance of FLT3-ITD harbouring additional point mutations, notably the previously refractory F691I mutation.
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 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

Patents

08470851
2
08778942
2
20070191376
4
CN103570724A
2
US20140343282
2
WO2015001098A1
2

Sample Use Guides

In Vivo Use Guide
Sources: uri2
Curator's Comment: comment
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.
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 [ORANGE BOOK]
Common Name English
Ponatinib hydrochloride [WHO-DD]
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 Fri Dec 15 18:20:08 GMT 2023 , Edited by admin on Fri Dec 15 18:20:08 GMT 2023
NCI_THESAURUS C1742
Created by admin on Fri Dec 15 18:20:08 GMT 2023 , Edited by admin on Fri Dec 15 18:20:08 GMT 2023
EMA ASSESSMENT REPORTS ICLUSIG (AUTHORIZED: LEUKEMIA, LYMPHOID)
Created by admin on Fri Dec 15 18:20:08 GMT 2023 , Edited by admin on Fri Dec 15 18:20:08 GMT 2023
NCI_THESAURUS C155700
Created by admin on Fri Dec 15 18:20:08 GMT 2023 , Edited by admin on Fri Dec 15 18:20:08 GMT 2023
Code System Code Type Description
ChEMBL
CHEMBL1171837
Created by admin on Fri Dec 15 18:20:08 GMT 2023 , Edited by admin on Fri Dec 15 18:20:08 GMT 2023
PRIMARY
MERCK INDEX
m11700
Created by admin on Fri Dec 15 18:20:08 GMT 2023 , Edited by admin on Fri Dec 15 18:20:08 GMT 2023
PRIMARY
USAN
XX-35
Created by admin on Fri Dec 15 18:20:08 GMT 2023 , Edited by admin on Fri Dec 15 18:20:08 GMT 2023
PRIMARY
FDA UNII
96R6PU3D8J
Created by admin on Fri Dec 15 18:20:08 GMT 2023 , Edited by admin on Fri Dec 15 18:20:08 GMT 2023
PRIMARY
PUBCHEM
46908927
Created by admin on Fri Dec 15 18:20:08 GMT 2023 , Edited by admin on Fri Dec 15 18:20:08 GMT 2023
PRIMARY
EVMPD
SUB121686
Created by admin on Fri Dec 15 18:20:08 GMT 2023 , Edited by admin on Fri Dec 15 18:20:08 GMT 2023
PRIMARY
CAS
1114544-31-8
Created by admin on Fri Dec 15 18:20:08 GMT 2023 , Edited by admin on Fri Dec 15 18:20:08 GMT 2023
PRIMARY
RXCUI
1364953
Created by admin on Fri Dec 15 18:20:08 GMT 2023 , Edited by admin on Fri Dec 15 18:20:08 GMT 2023
PRIMARY RxNorm
EPA CompTox
DTXSID50149655
Created by admin on Fri Dec 15 18:20:08 GMT 2023 , Edited by admin on Fri Dec 15 18:20:08 GMT 2023
PRIMARY
DAILYMED
96R6PU3D8J
Created by admin on Fri Dec 15 18:20:08 GMT 2023 , Edited by admin on Fri Dec 15 18:20:08 GMT 2023
PRIMARY
NCI_THESAURUS
C78194
Created by admin on Fri Dec 15 18:20:08 GMT 2023 , Edited by admin on Fri Dec 15 18:20:08 GMT 2023
PRIMARY
DRUG BANK
DBSALT000142
Created by admin on Fri Dec 15 18:20:08 GMT 2023 , Edited by admin on Fri Dec 15 18:20:08 GMT 2023
PRIMARY
SMS_ID
100000144869
Created by admin on Fri Dec 15 18:20:08 GMT 2023 , Edited by admin on Fri Dec 15 18:20:08 GMT 2023
PRIMARY
ACTIVE MOIETY
Structure of PONATINIB
NIH
NCATS
PRIVACY ACT
ACCESSIBILITY
DISCLAIMER
HHS VULNERABILITY DISCLOSURE
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