Identification

Name
Ponatinib
Accession Number
DB08901  (DB06300)
Type
Small Molecule
Groups
Approved, Investigational
Description

Ponatinib is a novel Bcr-Abl tyrosine kinase inhibitor that is especially effective against the T315I mutation for the treatment of chronic myeloid leukemia. FDA approved on December 14, 2012.

Structure
Thumb
Synonyms
  • Ponatinib
  • Ponatinibum
External IDs
AP 24534 / AP-24534 / AP24534
Product Ingredients
IngredientUNIICASInChI Key
Ponatinib hydrochloride96R6PU3D8J1114544-31-8BWTNNZPNKQIADY-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
IclusigTablet, film coated45 mg/1OralMillennium Pharmaceuticals, Inc.2012-12-14Not applicableUs
IclusigTablet15 mgOralAriad Pharmaceuticals2015-08-21Not applicableCanada
IclusigTablet, film coated15 mg/1OralAriad Pharmaceuticals2012-12-142020-07-26Us
IclusigTablet, film coated30 mg/1OralAriad Pharmaceuticals2015-04-222020-07-26Us
IclusigTablet45 mgOralAriad Pharmaceuticals2016-01-07Not applicableCanada
IclusigTablet, film coated30 mg/1OralMillennium Pharmaceuticals, Inc.2015-04-22Not applicableUs
IclusigTablet, film coated45 mg/1OralAriad Pharmaceuticals2012-12-142020-07-26Us
IclusigTablet, film coated15 mg/1OralMillennium Pharmaceuticals, Inc.2012-12-14Not applicableUs
Categories
UNII
4340891KFS
CAS number
943319-70-8
Weight
Average: 532.5595
Monoisotopic: 532.219844131
Chemical Formula
C29H27F3N6O
InChI Key
PHXJVRSECIGDHY-UHFFFAOYSA-N
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)
IUPAC Name
3-(2-{imidazo[1,2-b]pyridazin-3-yl}ethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide
SMILES
CN1CCN(CC2=CC=C(NC(=O)C3=CC(C#CC4=CN=C5C=CC=NN45)=C(C)C=C3)C=C2C(F)(F)F)CC1

Pharmacology

Indication

Ponatinib is indicated for the treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy.

Associated Conditions
Pharmacodynamics
Not Available
Mechanism of action

Ponatinib is a multi-target kinase inhibitor. Its primary cellular target is the Bcr-Abl tyrosine kinase protein which is constitutively active and promotes the progression of CML. This protein arises from the fused Bcr and Abl gene- what is commonly known as the Philadelphia chromosome. Ponatinib is unique in that it is especially useful in the treatment of resistant CML because it inhibits the tyrosine kinase activity of Abl and T315I mutant kinases. The T315I mutation confers resistance in cells as it prevents other Bcr-Abl inhibitors from binding to the Abl kinase. Other targets that ponatinib inhibits are members of the VEGFR, PDGFR, FGFR, EPH receptors and SRC families of kinases, and KIT, RET, TIE2, and FLT3. A decrease in tumour size expressing native or T315I mutant BCR-ABL have been observed in rats.

TargetActionsOrganism
ATyrosine-protein kinase ABL1
inhibitor
Human
ABreakpoint cluster region protein
inhibitor
Human
UMast/stem cell growth factor receptor Kit
inhibitor
Human
UProto-oncogene tyrosine-protein kinase receptor Ret
inhibitor
Human
UAngiopoietin-1 receptor
inhibitor
Human
UReceptor-type tyrosine-protein kinase FLT3
inhibitor
Human
UFibroblast growth factor receptor 1
inhibitor
Human
UFibroblast growth factor receptor 2
inhibitor
Human
UFibroblast growth factor receptor 3
inhibitor
Human
UFibroblast growth factor receptor 4
inhibitor
Human
UTyrosine-protein kinase Lck
inhibitor
Human
UProto-oncogene tyrosine-protein kinase Src
inhibitor
Human
UTyrosine-protein kinase Lyn
inhibitor
Human
UVascular endothelial growth factor receptor 2
inhibitor
Human
UPlatelet-derived growth factor receptor alpha
inhibitor
Human
Absorption

The absolute bioavailability of ponatinib is unknown. Peak concentrations of ponatinib are observed within 6 hours after Iclusig oral administration. Food does not affect absorption of food. The aqueous solubility of ponatinib is pH dependent, with higher pH resulting in lower solubility. When 45 mg of ponatinib is given to cancer patients, the pharmacokinetic parameters are as follows: Cmax = 73 ng/mL; AUC = 1253 ng•hr/mL;

Volume of distribution

After oral administration of 45 mg ponatinib once daily for 28 days in cancer patients, the steady state volume of distribution is 1223 L. Ponatinib is a weak substrate for P-gp and ABCG2.

Protein binding

> 99% bound to plasma proteins.

Metabolism

At least 64% of a ponatinib dose undergoes phase I and phase II metabolism. CYP3A4 and to a lesser extent CYP2C8, CYP2D6 and CYP3A5 are involved in the phase I metabolism of ponatinib in vitro. Ponatinib is also metabolized by esterases and/or amidases.

Route of elimination

Ponatinib is mainly eliminated via feces. Following a single oral dose of [14C]-labeled ponatinib, approximately 87% of the radioactive dose is recovered in the feces and approximately 5% in the urine.

Half life

After oral administration of 45 mg ponatinib once daily for 28 days in cancer patients, the terminal elimination half-life is 24 hours (range of 12 - 66 hours).

Clearance
Not Available
Toxicity

The most common non-hematologic adverse reactions (≥ 20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia.

Affected organisms
  • Humans and other mammals
Pathways
PathwayCategory
Ponatinib Inhibition of BCR-ABLDrug action
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be decreased when combined with Ponatinib.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Ponatinib.
2-MethoxyethanolThe risk or severity of adverse effects can be increased when 2-Methoxyethanol is combined with Ponatinib.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Ponatinib.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Ponatinib.
4-MethoxyamphetamineThe metabolism of Ponatinib can be decreased when combined with 4-Methoxyamphetamine.
5-androstenedioneThe metabolism of Ponatinib can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide BThe metabolism of Ponatinib can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Ponatinib.
7-ethyl-10-hydroxycamptothecinThe metabolism of Ponatinib can be decreased when combined with 7-ethyl-10-hydroxycamptothecin.
Food Interactions
Not Available

References

General References
  1. Reddy EP, Aggarwal AK: The ins and outs of bcr-abl inhibition. Genes Cancer. 2012 May;3(5-6):447-54. doi: 10.1177/1947601912462126. [PubMed:23226582]
External Links
Human Metabolome Database
HMDB0240214
KEGG Drug
D09950
PubChem Compound
24826799
PubChem Substance
175427142
ChemSpider
24747381
BindingDB
50322535
ChEBI
78543
ChEMBL
CHEMBL1171837
PharmGKB
PA165980594
HET
0LI
Drugs.com
Drugs.com Drug Page
Wikipedia
Ponatinib
ATC Codes
L01XE24 — Ponatinib
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
PDB Entries
3ik3 / 3oxz / 3zos / 4c8b / 4qrc / 4tyj / 4u0i / 4uxq / 4v01 / 4v04
FDA label
Download (295 KB)
MSDS
Download (98 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentChronic Chronic myelogenous leukemia / Malignancies, Hematologic1
1RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL) / Leukemia Acute Myeloid Leukemia (AML) / Untreated Adult Acute Myeloid Leukemia1
1, 2CompletedTreatmentChronic Myeloid Leukemia (CML) / Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL)1
1, 2RecruitingTreatmentAcute Lymphoblastic Leukaemia Recurrent / Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive / Leukemias / Philadelphia Chromosome Positive / Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive / Refractory Acute Lymphoblastic Leukemia / Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive / T(9;22)1
1, 2RecruitingTreatmentAcute Myeloid Lukemia1
1, 2RecruitingTreatmentKRAS Gene Mutation / Lung Cancer Non-Small Cell Cancer (NSCLC)1
1, 2WithdrawnTreatmentFLT3-Mutated Acute Myeloid Leukemia / FLT3-Mutated High-Risk Myelodysplastic Syndrome / Leukemias1
2Active Not RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL) / BCR-ABL Positive / Philadelphia Positive1
2Active Not RecruitingTreatmentChronic Myeloid Leukemia (CML) / Ph+ Acute Lymphoblastic Leukemia / Ph+ Acute Lymphoblastic Leukemia (ALL)1
2Active Not RecruitingTreatmentChronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive / Leukemias / Philadelphia Chromosome Positive, BCR-ABL1 Positive Chronic Myelogenous Leukemia / Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive1
2Active Not RecruitingTreatmentMalignant hepatobiliary neoplasms1
2CompletedTreatmentGIST1
2CompletedTreatmentGlioblastomas1
2CompletedTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
2Not Yet RecruitingTreatmentLeukemia Acute Myeloid Leukemia (AML)1
2RecruitingTreatmentAcute Lymphoblastic Leukaemia Recurrent / Acute Lymphoblastic Leukaemias (ALL) / Acute Myeloid Leukemia With BCR-ABL1 / Philadelphia Chromosome Positive / Refractory Acute Lymphoblastic Leukemia1
2RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL) / Acute Myelogenous Leukaemia (AML) / Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome / Chronic Myelomonocytic Leukemia / Myelodysplastic Syndrome / Recurrent Adult Acute Lymphoblastic Leukemia / Recurrent Adult Acute Myeloid Leukemia / Refractory Adult Acute Lymphoblastic Leukemia1
2RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL) / Adult Acute Lymphoblastic Leukemia in Complete Remission / B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1 / Leukemias / Philadelphia Chromosome Positive / Untreated Adult Acute Lymphoblastic Leukemia1
2RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL) / Malignant Neoplasms Stated as Primary Lymphoid Haematopoietic1
2RecruitingTreatmentAdenocarcinoma of the Lung / Extensive Stage Small Cell Lung Cancer / Limited Stage Small Cell Lung Cancer / Non-Small Cell Lung Cancer Recurrent / Refractory Small cell lung cancer / Stage IIIA Non-Small Cell Lung Cancer / Stage IIIb Non-small Cell Lung Cancer / Stage IV Non-Small Cell Lung Cancer1
2RecruitingTreatmentAdults / Chronic Myeloid Leukemia (CML) / Chronic Phase1
2RecruitingTreatmentAll1
2RecruitingTreatmentMyeloid Leukemia, Chronic, Chronic Phase1
2RecruitingTreatmentNeoplasms, Malignant1
2TerminatedTreatmentLeukemias1
2TerminatedTreatmentNeoplasms, Thyroid1
2, 3TerminatedTreatmentNon-Small Cell Lung Cancer, Head and Neck Cancer1
3Active Not RecruitingTreatmentChronic Phase Chronic Myeloid Leukemia1
3RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL) / Acute Lymphocytic Leukemia (ALL) / Leukaemia, Lymphoblastic / Leukemia, Lymphoblastic, Acute, Philadelphia-Positive / Lymphoblastic Leukemia, Acute, Adult / Ph1 Chromosome1
3TerminatedTreatmentChronic Myeloid Leukemia (CML)1
Not AvailableApproved for MarketingNot AvailableChronic Myeloid Leukemia (CML) / Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL)1
Not AvailableCompletedNot AvailableLeukemias1
Not AvailableNo Longer AvailableNot AvailableChronic Myeloid Leukemia (CML) / Philadelphia Chromosome Positive (Ph+) Leukemias1
Not AvailableRecruitingNot AvailableAcute Lymphoblastic Leukaemias (ALL)1
Not AvailableRecruitingNot AvailableChronic Myeloid Leukemia (CML) / Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia1
Not AvailableRecruitingNot AvailableChronic Myeloid Leukemia (CML) / Philadelphia Positive1
Not AvailableWithdrawnTreatmentNeoplasms, Endometrial1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral15 mg
TabletOral45 mg
Tablet, film coatedOral15 mg/1
Tablet, film coatedOral30 mg/1
Tablet, film coatedOral45 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US9029533No2015-05-122026-12-22Us
US8114874No2012-02-142026-12-22Us
US9493470No2016-11-152033-12-12Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
pKa2.77 and 7.8 FDA label
Predicted Properties
PropertyValueSource
Water Solubility0.00295 mg/mLALOGPS
logP3.94ALOGPS
logP4.97ChemAxon
logS-5.3ALOGPS
pKa (Strongest Acidic)11.36ChemAxon
pKa (Strongest Basic)8.03ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area65.77 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity152.63 m3·mol-1ChemAxon
Polarizability55.69 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9444
Caco-2 permeable-0.5985
P-glycoprotein substrateSubstrate0.7205
P-glycoprotein inhibitor IInhibitor0.8197
P-glycoprotein inhibitor IIInhibitor0.9125
Renal organic cation transporterInhibitor0.5
CYP450 2C9 substrateNon-substrate0.8612
CYP450 2D6 substrateNon-substrate0.7047
CYP450 3A4 substrateSubstrate0.7636
CYP450 1A2 substrateNon-inhibitor0.8592
CYP450 2C9 inhibitorNon-inhibitor0.6804
CYP450 2D6 inhibitorNon-inhibitor0.764
CYP450 2C19 inhibitorInhibitor0.5563
CYP450 3A4 inhibitorNon-inhibitor0.5613
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.6686
Ames testNon AMES toxic0.5331
CarcinogenicityNon-carcinogens0.8254
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.8377 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8253
hERG inhibition (predictor II)Inhibitor0.7493
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-014i-1490100000-181c36e7111f139a09cd
MS/MS Spectrum - , positiveLC-MS/MSsplash10-03e9-0290150000-ab2ecf1ddb48e116ad86

Taxonomy

Description
This compound belongs to the class of organic compounds known as benzanilides. These are aromatic compounds containing an anilide group in which the carboxamide group is substituted with a benzene ring. They have the general structure RNC(=O)R', where R,R'= benzene.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Anilides
Direct Parent
Benzanilides
Alternative Parents
Trifluoromethylbenzenes / p-Toluamides / Benzamides / Benzoyl derivatives / Benzylamines / Phenylmethylamines / N-methylpiperazines / Aralkylamines / N-substituted imidazoles / Pyridazines and derivatives
show 11 more
Substituents
Benzanilide / Trifluoromethylbenzene / Benzamide / Benzoic acid or derivatives / P-toluamide / Toluamide / Benzoyl / Benzylamine / Phenylmethylamine / Toluene
show 31 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
benzamides, acetylenic compound, N-methylpiperazine, (trifluoromethyl)benzenes, imidazopyridazine (CHEBI:78543)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Syntaxin binding
Specific Function
Non-receptor tyrosine-protein kinase that plays a role in many key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility a...
Gene Name
ABL1
Uniprot ID
P00519
Uniprot Name
Tyrosine-protein kinase ABL1
Molecular Weight
122871.435 Da
References
  1. Iqbal Z, Aleem A, Iqbal M, Naqvi MI, Gill A, Taj AS, Qayyum A, ur-Rehman N, Khalid AM, Shah IH, Khalid M, Haq R, Khan M, Baig SM, Jamil A, Abbas MN, Absar M, Mahmood A, Rasool M, Akhtar T: Sensitive detection of pre-existing BCR-ABL kinase domain mutations in CD34+ cells of newly diagnosed chronic-phase chronic myeloid leukemia patients is associated with imatinib resistance: implications in the post-imatinib era. PLoS One. 2013;8(2):e55717. doi: 10.1371/journal.pone.0055717. Epub 2013 Feb 8. [PubMed:23409026]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Rho guanyl-nucleotide exchange factor activity
Specific Function
GTPase-activating protein for RAC1 and CDC42. Promotes the exchange of RAC or CDC42-bound GDP by GTP, thereby activating them. Displays serine/threonine kinase activity.
Gene Name
BCR
Uniprot ID
P11274
Uniprot Name
Breakpoint cluster region protein
Molecular Weight
142818.07 Da
References
  1. Iqbal Z, Aleem A, Iqbal M, Naqvi MI, Gill A, Taj AS, Qayyum A, ur-Rehman N, Khalid AM, Shah IH, Khalid M, Haq R, Khan M, Baig SM, Jamil A, Abbas MN, Absar M, Mahmood A, Rasool M, Akhtar T: Sensitive detection of pre-existing BCR-ABL kinase domain mutations in CD34+ cells of newly diagnosed chronic-phase chronic myeloid leukemia patients is associated with imatinib resistance: implications in the post-imatinib era. PLoS One. 2013;8(2):e55717. doi: 10.1371/journal.pone.0055717. Epub 2013 Feb 8. [PubMed:23409026]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Transmembrane receptor protein tyrosine kinase activity
Specific Function
Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell main...
Gene Name
KIT
Uniprot ID
P10721
Uniprot Name
Mast/stem cell growth factor receptor Kit
Molecular Weight
109863.655 Da
References
  1. Gleixner KV, Peter B, Blatt K, Suppan V, Reiter A, Radia D, Hadzijusufovic E, Valent P: Synergistic growth-inhibitory effects of ponatinib and midostaurin (PKC412) on neoplastic mast cells carrying KIT D816V. Haematologica. 2013 Sep;98(9):1450-7. doi: 10.3324/haematol.2012.079202. Epub 2013 Mar 28. [PubMed:23539538]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Transmembrane receptor protein tyrosine kinase activity
Specific Function
Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation upon binding with glial cell de...
Gene Name
RET
Uniprot ID
P07949
Uniprot Name
Proto-oncogene tyrosine-protein kinase receptor Ret
Molecular Weight
124317.465 Da
References
  1. De Falco V, Buonocore P, Muthu M, Torregrossa L, Basolo F, Billaud M, Gozgit JM, Carlomagno F, Santoro M: Ponatinib (AP24534) is a novel potent inhibitor of oncogenic RET mutants associated with thyroid cancer. J Clin Endocrinol Metab. 2013 May;98(5):E811-9. doi: 10.1210/jc.2012-2672. Epub 2013 Mar 22. [PubMed:23526464]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Transmembrane receptor protein tyrosine kinase activity
Specific Function
Tyrosine-protein kinase that acts as cell-surface receptor for ANGPT1, ANGPT2 and ANGPT4 and regulates angiogenesis, endothelial cell survival, proliferation, migration, adhesion and cell spreading...
Gene Name
TEK
Uniprot ID
Q02763
Uniprot Name
Angiopoietin-1 receptor
Molecular Weight
125829.005 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Vascular endothelial growth factor-activated receptor activity
Specific Function
Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells...
Gene Name
FLT3
Uniprot ID
P36888
Uniprot Name
Receptor-type tyrosine-protein kinase FLT3
Molecular Weight
112902.51 Da
References
  1. Smith CC, Lasater EA, Zhu X, Lin KC, Stewart WK, Damon LE, Salerno S, Shah NP: Activity of ponatinib against clinically-relevant AC220-resistant kinase domain mutants of FLT3-ITD. Blood. 2013 Apr 18;121(16):3165-71. doi: 10.1182/blood-2012-07-442871. Epub 2013 Feb 21. [PubMed:23430109]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Protein tyrosine kinase activity
Specific Function
Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation ...
Gene Name
FGFR1
Uniprot ID
P11362
Uniprot Name
Fibroblast growth factor receptor 1
Molecular Weight
91866.935 Da
References
  1. Ren M, Hong M, Liu G, Wang H, Patel V, Biddinger P, Silva J, Cowell J, Hao Z: Novel FGFR inhibitor ponatinib suppresses the growth of non-small cell lung cancer cells overexpressing FGFR1. Oncol Rep. 2013 Jun;29(6):2181-90. doi: 10.3892/or.2013.2386. Epub 2013 Apr 4. [PubMed:23563700]
  2. Gozgit JM, Squillace RM, Wongchenko MJ, Miller D, Wardwell S, Mohemmad Q, Narasimhan NI, Wang F, Clackson T, Rivera VM: Combined targeting of FGFR2 and mTOR by ponatinib and ridaforolimus results in synergistic antitumor activity in FGFR2 mutant endometrial cancer models. Cancer Chemother Pharmacol. 2013 May;71(5):1315-23. doi: 10.1007/s00280-013-2131-z. Epub 2013 Mar 7. [PubMed:23468082]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Protein tyrosine kinase activity
Specific Function
Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation, migration and apoptosi...
Gene Name
FGFR2
Uniprot ID
P21802
Uniprot Name
Fibroblast growth factor receptor 2
Molecular Weight
92024.29 Da
References
  1. Gozgit JM, Squillace RM, Wongchenko MJ, Miller D, Wardwell S, Mohemmad Q, Narasimhan NI, Wang F, Clackson T, Rivera VM: Combined targeting of FGFR2 and mTOR by ponatinib and ridaforolimus results in synergistic antitumor activity in FGFR2 mutant endometrial cancer models. Cancer Chemother Pharmacol. 2013 May;71(5):1315-23. doi: 10.1007/s00280-013-2131-z. Epub 2013 Mar 7. [PubMed:23468082]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Protein tyrosine kinase activity
Specific Function
Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation and apoptosis. Plays an...
Gene Name
FGFR3
Uniprot ID
P22607
Uniprot Name
Fibroblast growth factor receptor 3
Molecular Weight
87708.905 Da
References
  1. Gozgit JM, Squillace RM, Wongchenko MJ, Miller D, Wardwell S, Mohemmad Q, Narasimhan NI, Wang F, Clackson T, Rivera VM: Combined targeting of FGFR2 and mTOR by ponatinib and ridaforolimus results in synergistic antitumor activity in FGFR2 mutant endometrial cancer models. Cancer Chemother Pharmacol. 2013 May;71(5):1315-23. doi: 10.1007/s00280-013-2131-z. Epub 2013 Mar 7. [PubMed:23468082]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Protein tyrosine kinase activity
Specific Function
Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays a role in the regulation of cell proliferation, differentiation and migration, and in regulation o...
Gene Name
FGFR4
Uniprot ID
P22455
Uniprot Name
Fibroblast growth factor receptor 4
Molecular Weight
87953.535 Da
References
  1. Gozgit JM, Squillace RM, Wongchenko MJ, Miller D, Wardwell S, Mohemmad Q, Narasimhan NI, Wang F, Clackson T, Rivera VM: Combined targeting of FGFR2 and mTOR by ponatinib and ridaforolimus results in synergistic antitumor activity in FGFR2 mutant endometrial cancer models. Cancer Chemother Pharmacol. 2013 May;71(5):1315-23. doi: 10.1007/s00280-013-2131-z. Epub 2013 Mar 7. [PubMed:23468082]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sh2 domain binding
Specific Function
Non-receptor tyrosine-protein kinase that plays an essential role in the selection and maturation of developing T-cells in the thymus and in the function of mature T-cells. Plays a key role in T-ce...
Gene Name
LCK
Uniprot ID
P06239
Uniprot Name
Tyrosine-protein kinase Lck
Molecular Weight
58000.15 Da
References
  1. Gushwa NN, Kang S, Chen J, Taunton J: Selective targeting of distinct active site nucleophiles by irreversible SRC-family kinase inhibitors. J Am Chem Soc. 2012 Dec 19;134(50):20214-7. doi: 10.1021/ja310659j. Epub 2012 Dec 4. [PubMed:23190395]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sh3/sh2 adaptor activity
Specific Function
Non-receptor protein tyrosine kinase which is activated following engagement of many different classes of cellular receptors including immune response receptors, integrins and other adhesion recept...
Gene Name
SRC
Uniprot ID
P12931
Uniprot Name
Proto-oncogene tyrosine-protein kinase Src
Molecular Weight
59834.295 Da
References
  1. O'Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F, Adrian LT, Zhou T, Huang WS, Xu Q, Metcalf CA 3rd, Tyner JW, Loriaux MM, Corbin AS, Wardwell S, Ning Y, Keats JA, Wang Y, Sundaramoorthi R, Thomas M, Zhou D, Snodgrass J, Commodore L, Sawyer TK, Dalgarno DC, Deininger MW, Druker BJ, Clackson T: AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009 Nov 6;16(5):401-12. doi: 10.1016/j.ccr.2009.09.028. [PubMed:19878872]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Receptor signaling protein tyrosine kinase activity
Specific Function
Non-receptor tyrosine-protein kinase that transmits signals from cell surface receptors and plays an important role in the regulation of innate and adaptive immune responses, hematopoiesis, respons...
Gene Name
LYN
Uniprot ID
P07948
Uniprot Name
Tyrosine-protein kinase Lyn
Molecular Weight
58573.595 Da
References
  1. O'Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F, Adrian LT, Zhou T, Huang WS, Xu Q, Metcalf CA 3rd, Tyner JW, Loriaux MM, Corbin AS, Wardwell S, Ning Y, Keats JA, Wang Y, Sundaramoorthi R, Thomas M, Zhou D, Snodgrass J, Commodore L, Sawyer TK, Dalgarno DC, Deininger MW, Druker BJ, Clackson T: AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009 Nov 6;16(5):401-12. doi: 10.1016/j.ccr.2009.09.028. [PubMed:19878872]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Vascular endothelial growth factor-activated receptor activity
Specific Function
Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD. Plays an essential role in the regulation of angiogenesis, vascular development, vascular permeability, and ...
Gene Name
KDR
Uniprot ID
P35968
Uniprot Name
Vascular endothelial growth factor receptor 2
Molecular Weight
151525.555 Da
References
  1. O'Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F, Adrian LT, Zhou T, Huang WS, Xu Q, Metcalf CA 3rd, Tyner JW, Loriaux MM, Corbin AS, Wardwell S, Ning Y, Keats JA, Wang Y, Sundaramoorthi R, Thomas M, Zhou D, Snodgrass J, Commodore L, Sawyer TK, Dalgarno DC, Deininger MW, Druker BJ, Clackson T: AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009 Nov 6;16(5):401-12. doi: 10.1016/j.ccr.2009.09.028. [PubMed:19878872]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Vascular endothelial growth factor-activated receptor activity
Specific Function
Tyrosine-protein kinase that acts as a cell-surface receptor for PDGFA, PDGFB and PDGFC and plays an essential role in the regulation of embryonic development, cell proliferation, survival and chem...
Gene Name
PDGFRA
Uniprot ID
P16234
Uniprot Name
Platelet-derived growth factor receptor alpha
Molecular Weight
122668.46 Da
References
  1. O'Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F, Adrian LT, Zhou T, Huang WS, Xu Q, Metcalf CA 3rd, Tyner JW, Loriaux MM, Corbin AS, Wardwell S, Ning Y, Keats JA, Wang Y, Sundaramoorthi R, Thomas M, Zhou D, Snodgrass J, Commodore L, Sawyer TK, Dalgarno DC, Deininger MW, Druker BJ, Clackson T: AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009 Nov 6;16(5):401-12. doi: 10.1016/j.ccr.2009.09.028. [PubMed:19878872]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Lin, Kostov R, Huang JT, Henderson CJ, Wolf CR: Novel Pathways of Ponatinib Disposition Catalyzed By CYP1A1 Involving Generation of Potentially Toxic Metabolites. J Pharmacol Exp Ther. 2017 Oct;363(1):12-19. doi: 10.1124/jpet.117.243246. [PubMed:28882992]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. Price KE, Saleem N, Lee G, Steinberg M: Potential of ponatinib to treat chronic myeloid leukemia and acute lymphoblastic leukemia. Onco Targets Ther. 2013 Aug 20;6:1111-8. doi: 10.2147/OTT.S36980. eCollection 2013. [PubMed:23986642]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da

Drug created on June 08, 2013 16:03 / Updated on December 18, 2018 05:46