PONATINIB HYDROCHLORIDE

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 Search

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

Molecular Formula	ClH
Molecular Weight	36.461
Charge	0
Count

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

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	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 8297
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 8297	0.4 nM [IC50]
mitochondrion inheritance 2 Target ID: GO:0000001 Target Organism: Homo sapiens (Human) Sources: http://helloworld.com
cox1 2 Target ID: 123.0 Sources: https://pubmed.ncbi.nlm.nih.gov/32915792/

Conditions

Condition	Modality	Highest Phase	Product
Chronic myeloid leukemia 25 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf	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
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 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

C_max

Value	Dose	Analyte	Population
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

Value	Dose	Analyte	Population
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

T_1/2

Value	Dose	Co-administered	Analyte	Population
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

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 unknown	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse 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

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737 inducer 781	inhibitor 1767	substrate 1217 inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other 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

Target	Modality	Activity	Metabolite
CYP3A4 1925	inhibitor 3277		test 2
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000ClinPharmR.pdf	little [IC50 10.8 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000ClinPharmR.pdf	little [IC50 11.6 uM]
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000ClinPharmR.pdf	little [IC50 13.3 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000ClinPharmR.pdf	little [IC50 5.2 uM]
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000ClinPharmR.pdf	little [IC50 5.6 uM]
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000ClinPharmR.pdf	little [IC50 6.1 uM]
CYP3A 298	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000ClinPharmR.pdf	little [IC50 8.3 uM]
OAT1 603	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000ClinPharmR.pdf	no
OAT3 644	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000ClinPharmR.pdf	no
OATP1B1 803	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000ClinPharmR.pdf	no
OATP1B3 715	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000ClinPharmR.pdf	no
OCT1 543	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000ClinPharmR.pdf	no
OCT2 648	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000ClinPharmR.pdf	no
CYP3A4 1925	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000ClinPharmR.pdf	yes [Activation 0.6 uM]
BCRP 773	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000ClinPharmR.pdf	yes [IC50 0.013 uM]
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000ClinPharmR.pdf	yes [IC50 0.49 uM]
BSEP 403	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000ClinPharmR.pdf	yes [IC50 32 uM]

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000ClinPharmR.pdf	major	yes (co-administration study) Comment: ketoconazole increased cmax of ponatinib by 47%, auc by 78% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000ClinPharmR.pdf
CYP2C8 693	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000ClinPharmR.pdf	minor
CYP2D6 1217	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000ClinPharmR.pdf	minor
CYP3A5 395	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000ClinPharmR.pdf	minor
OATP1B1 406	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000ClinPharmR.pdf	no
OATP1B3 350	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000ClinPharmR.pdf	no
OCT1 327	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000ClinPharmR.pdf	no
BCRP 561	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000ClinPharmR.pdf	weak
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000ClinPharmR.pdf	weak

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000PharmR.pdf

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
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

Title	Date	PubMed
		252160515
Infectious influenza A and B virus variants with long carboxyl terminal deletions in the NS1 polypeptides.	1987 Feb	3811235
Inhibitors of ABL and the ABL-T315I mutation.	2008	18673174
AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance.	2009 Nov 6	19878872
Structural mechanism of the Pan-BCR-ABL inhibitor ponatinib (AP24534): lessons for overcoming kinase inhibitor resistance.	2011 Jan	21118377
Potent activity of ponatinib (AP24534) in models of FLT3-driven acute myeloid leukemia and other hematologic malignancies.	2011 Jun	21482694
Discovery of 5-(arenethynyl) hetero-monocyclic derivatives as potent inhibitors of BCR-ABL including the T315I gatekeeper mutant.	2011 Jun 15	21561767
Discovery of 5-(arenethynyl) hetero-monocyclic derivatives as potent inhibitors of BCR-ABL including the T315I gatekeeper mutant.	2011 Jun 15	21561767
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	21908430
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	21908430
Ponatinib is active against imatinib-resistant mutants of FIP1L1-PDGFRA and KIT, and against FGFR1-derived fusion kinases.	2012 Jul	22301675
Ponatinib is active against imatinib-resistant mutants of FIP1L1-PDGFRA and KIT, and against FGFR1-derived fusion kinases.	2012 Jul	22301675
Ponatinib may overcome resistance of FLT3-ITD harbouring additional point mutations, notably the previously refractory F691I mutation.	2012 May	22409268
The ins and outs of bcr-abl inhibition.	2012 May	23226582
Ponatinib may overcome resistance of FLT3-ITD harbouring additional point mutations, notably the previously refractory F691I mutation.	2012 May	22409268
Ponatinib as targeted therapy for FGFR1 fusions associated with the 8p11 myeloproliferative syndrome.	2013 Jan	22875613
Ponatinib suppresses the development of myeloid and lymphoid malignancies associated with FGFR1 abnormalities.	2013 Jan	22781593
Ponatinib as targeted therapy for FGFR1 fusions associated with the 8p11 myeloproliferative syndrome.	2013 Jan	22875613
Ponatinib suppresses the development of myeloid and lymphoid malignancies associated with FGFR1 abnormalities.	2013 Jan	22781593
Ponatinib is a potent inhibitor of wild-type and drug-resistant gatekeeper mutant RET kinase.	2013 Sep 5	23811235
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	25053825
A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease.	2015 Dec	26502155
A multi-parameter in vitro screen in human stem cell-derived cardiomyocytes identifies ponatinib-induced structural and functional cardiac toxicity.	2015 Jan	25304212

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 `Fri Dec 15 18:20:08 GMT 2023` Edited by `admin` on `Fri Dec 15 18:20:08 GMT 2023`
Record UNII	96R6PU3D8J
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

PONATINIB HYDROCHLORIDE

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