ponatinib

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Ligands
ponatinib

GtoPdb Ligand ID: 5890

Synonyms: AP24534 | Iclusig®

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.

View interactive charts of activity data across species

View more information in the IUPHAR Pharmacology Education Project: ponatinib

ponatinib is commercially available from our sponsors

2D Structure

Physico-chemical Properties

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

SMILES / InChI / InChIKey

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)
InChI Key	PHXJVRSECIGDHY-UHFFFAOYSA-N

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No information available.

Summary of Clinical Use
Ponatinib is a multi-targeted tyrosine-kinase inhibitor approved for the treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph⁺ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy. For example, cases of CML which have the T315I mutation, are resistant to current therapies such as imatinib so ponatinib has been designed to be effective against these types of tumours. Final 5-year results of safety and efficacy in Ph+ leukemia as evaluated in Phase 2 study NCT01207440 are reported by Cortes et al. (2018) [1]. This analysis concludes that ponatinib is an effective treatment that produces durable and clinically significant responses, but also, that the risk of AOEs should be considered on a patient-by-patient basis to fully inform the decision to treat with ponatinib.

Summary of Clinical Use

Ponatinib is a multi-targeted tyrosine-kinase inhibitor approved for the treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph⁺ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy. For example, cases of CML which have the T315I mutation, are resistant to current therapies such as imatinib so ponatinib has been designed to be effective against these types of tumours. Final 5-year results of safety and efficacy in Ph+ leukemia as evaluated in Phase 2 study NCT01207440 are reported by Cortes et al. (2018) [1]. This analysis concludes that ponatinib is an effective treatment that produces durable and clinically significant responses, but also, that the risk of AOEs should be considered on a patient-by-patient basis to fully inform the decision to treat with ponatinib.

Mechanism Of Action and Pharmacodynamic Effects
The primary target for ponatinib is BCR-Abl, the abnormal tyrosine kinase that is the hallmark of CML and Ph⁺ALL. Ponatinib also inhibits the in vitro activity of other kinases including several receptor tyrosine kinases (eg KIT, RET, TIE2, and FLT3) and Src familiy kinases, at nanomolar concentrations.

Mechanism Of Action and Pharmacodynamic Effects

The primary target for ponatinib is BCR-Abl, the abnormal tyrosine kinase that is the hallmark of CML and Ph⁺ALL. Ponatinib also inhibits the in vitro activity of other kinases including several receptor tyrosine kinases (eg KIT, RET, TIE2, and FLT3) and Src familiy kinases, at nanomolar concentrations.

Clinical Trials
Clinical Trial ID	Title	Type	Source	Comment	References
NCT01207440	Ponatinib for Chronic Myeloid Leukemia (CML) Evaluation and Ph+ Acute Lymphoblastic Leukemia (ALL)	Phase 2 Interventional	Takeda

Pharmacokinetics
Absorption/Distribution
The absolute bioavailability of ponatinib is unknown. Peak concentrations of ponatinib are reached within 6 hours following oral administration. This drug can be taken with or without food. More than 99% of circulating ponatinib is bound to plasma proteins.
Biotransformation/Metabolism
In vitro studies show that CYP3A4 and to a lesser extent CYP2C8, CYP2D6 and CYP3A5 are involved in phase I metabolism of ponatinib and in total (phase I + phase II) more than 64% of a ponatinib dose is metabolised. Ponatinib is also metabolized by esterases and/or amidases.
Elimination
Ponatinib is mainly eliminated via feces (87%) and a minor amount is eliminated in the urine (5%).
Organ function impairment
As hepatic elimination is a major route of excretion, hepatic impairment may result in increased exposure to ponatinib. Use should therefore be avoided in patients with moderate to severe (Child-Pugh B or C) hepatic impairment unless the benefit outweighs the possible risk of ponatinib overexposure. Although renal excretion is not a major route of ponatinib elimination, the potential for moderate or severe renal impairment to affect hepatic elimination has not been determined

Pharmacokinetics

Absorption/Distribution

The absolute bioavailability of ponatinib is unknown. Peak concentrations of ponatinib are reached within 6 hours following oral administration. This drug can be taken with or without food. More than 99% of circulating ponatinib is bound to plasma proteins.

Biotransformation/Metabolism

In vitro studies show that CYP3A4 and to a lesser extent CYP2C8, CYP2D6 and CYP3A5 are involved in phase I metabolism of ponatinib and in total (phase I + phase II) more than 64% of a ponatinib dose is metabolised. Ponatinib is also metabolized by esterases and/or amidases.

Elimination

Ponatinib is mainly eliminated via feces (87%) and a minor amount is eliminated in the urine (5%).

Organ function impairment

As hepatic elimination is a major route of excretion, hepatic impairment may result in increased exposure to ponatinib. Use should therefore be avoided in patients with moderate to severe (Child-Pugh B or C) hepatic impairment unless the benefit outweighs the possible risk of ponatinib overexposure. Although renal excretion is not a major route of ponatinib elimination, the potential for moderate or severe renal impairment to affect hepatic elimination has not been determined