Identification

Name
Dovitinib
Accession Number
DB05928
Type
Small Molecule
Groups
Investigational
Description

Dovitinib is an orally active small molecule that exhibits potent inhibitory activity against multiple RTKs involved in tumor growth and angiogenesis. Preclinical data show that dovitinib works to inhibit multiple kinases associated with different cancers, including acute myeloid leukemia (AML) and multiple myeloma. Chiron currently has three ongoing Phase I clinical trials for dovitinib.

Structure
Thumb
Synonyms
Not Available
External IDs
TKI-258
Product Ingredients
IngredientUNIICASInChI Key
Dovitinib lactate hydrate69VKY8P7EA915769-50-5QDPVYZNVVQQULH-TYOUJGAFSA-N
Categories
UNII
I35H55G906
CAS number
405169-16-6
Weight
Average: 392.438
Monoisotopic: 392.176087483
Chemical Formula
C21H21FN6O
InChI Key
PIQCTGMSNWUMAF-UHFFFAOYSA-N
InChI
InChI=1S/C21H21FN6O/c1-27-7-9-28(10-8-27)12-5-6-14-16(11-12)25-20(24-14)18-19(23)17-13(22)3-2-4-15(17)26-21(18)29/h2-6,11H,7-10H2,1H3,(H,24,25)(H3,23,26,29)
IUPAC Name
4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-1,3-benzodiazol-2-yl]-1,2-dihydroquinolin-2-one
SMILES
CN1CCN(CC1)C1=CC=C2N=C(NC2=C1)C1=C(N)C2=C(NC1=O)C=CC=C2F

Pharmacology

Indication

Investigated for use/treatment in multiple myeloma and solid tumors.

Pharmacodynamics
Not Available
Mechanism of action

Unlike many kinase inhibitors that only target vascular endothelial growth factor (VEGF), Dovitinib inhibits receptors in the fibroblast growth factor (FGF ) pathway, as well as VEGF and platelet-derived growth factor (PDGF). FGF receptor tyrosine kinase inhibition is potentially of therapeutic significance to a group of myeloma patients whose cancer cells express high levels of surface FGF receptors.

TargetActionsOrganism
UNuclear receptor subfamily 1 group I member 2
suppressor
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AcebutololThe serum concentration of Acebutolol can be increased when it is combined with Dovitinib.
Acetylsalicylic acidThe serum concentration of Acetylsalicylic acid can be increased when it is combined with Dovitinib.
AlclometasoneThe metabolism of Alclometasone can be decreased when combined with Dovitinib.
AlfuzosinThe metabolism of Alfuzosin can be decreased when combined with Dovitinib.
AmcinonideThe metabolism of Amcinonide can be decreased when combined with Dovitinib.
AmitriptylineThe serum concentration of Amitriptyline can be increased when it is combined with Dovitinib.
Ascorbic acidThe serum concentration of Ascorbic acid can be increased when it is combined with Dovitinib.
AzithromycinThe metabolism of Azithromycin can be decreased when combined with Dovitinib.
BenzylpenicillinThe excretion of Benzylpenicillin can be decreased when combined with Dovitinib.
BetamethasoneThe serum concentration of Betamethasone can be increased when it is combined with Dovitinib.
Food Interactions
Not Available

References

General References
  1. Xin X, Abrams TJ, Hollenbach PW, Rendahl KG, Tang Y, Oei YA, Embry MG, Swinarski DE, Garrett EN, Pryer NK, Trudel S, Jallal B, Mendel DB, Heise CC: CHIR-258 is efficacious in a newly developed fibroblast growth factor receptor 3-expressing orthotopic multiple myeloma model in mice. Clin Cancer Res. 2006 Aug 15;12(16):4908-15. [PubMed:16914579]
  2. Trudel S, Li ZH, Wei E, Wiesmann M, Chang H, Chen C, Reece D, Heise C, Stewart AK: CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma. Blood. 2005 Apr 1;105(7):2941-8. Epub 2004 Dec 14. [PubMed:15598814]
External Links
PubChem Compound
9977819
PubChem Substance
347827750
ChemSpider
11530944
BindingDB
25118
ChEMBL
CHEMBL522892
HET
38O
Wikipedia
Fibroblast_growth_factor_receptor_1
PDB Entries
4tyi / 5a46 / 5am6 / 5am7 / 5owq

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingTreatmentFirst or Second Recurrence of Glioblastoma1
1CompletedTreatmentAdenocarcinoma of the Pancreas / Stage III Pancreatic Cancer / Stage IV Pancreatic Cancer / Unspecified Adult Solid Tumor, Protocol Specific1
1CompletedTreatmentAdvanced Solid Tumors1
1CompletedTreatmentAdvanced Solid Tumors, Excluding Breast Cancer2
1CompletedTreatmentAdvanced Solid Tumors / Excluding Breast Cancer1
1CompletedTreatmentCancers / Neoplasms / Tumors2
1CompletedTreatmentHepatic Impairment / Tumors, Solid1
1CompletedTreatmentMetastatic Clear Cell Renal Cancer1
1TerminatedTreatmentCancers / Neoplasms / Tumors1
1TerminatedTreatmentNon-small Cell Lung Cancer (NSCLC), Recurrent / Non-small Cell Lung Cancer (NSCLC), Stage IV / Non-Small Cell Lung Cancer Recurrent / Stage IV Non-Small Cell Lung Cancer1
1TerminatedTreatmentTumors, Solid1
1WithdrawnTreatmentDuct Cell Adenocarcinoma of the Pancreas / Recurrent Pancreatic Cancer / Stage III Pancreatic Cancer / Stage IV Pancreatic Cancer / Unspecified Adult Solid Tumor, Protocol Specific1
1WithdrawnTreatmentMultiple Myeloma (MM)1
1, 2CompletedTreatmentMalignant Neoplasm of Stomach1
1, 2TerminatedTreatmentCancer, Breast1
2Active Not RecruitingTreatmentAdvanced Metastatic Paraganglioma / Advanced Metastatic Pheochromocytoma / Recurrent Paraganglioma / Recurrent Pheochromocytoma / Unresectable Paraganglioma / Unresectable Pheochromocytoma1
2Active Not RecruitingTreatmentProstate Cancer1
2CompletedTreatmentACC / Metastatic Adenoid Cystic Carcinoma of the Salivary Glands / Recurrent Adenoid Cystic Carcinoma of the Salivary Glands / Salivary Gland Cancers1
2CompletedTreatmentAdenocarcinoma, Scirrhous / Linitis Plastica / Neoplasms / Neoplasms by Site / Stomach Diseases / Stomach Neoplasms1
2CompletedTreatmentAdrenocortical Carcinoma1
2CompletedTreatmentAdult Giant Cell Glioblastoma / Adult Glioblastoma / Adult Gliosarcoma / Recurrent Adult Brain Tumor1
2CompletedTreatmentCancer, Breast1
2CompletedTreatmentCarcinoma, Adenoid Cystic2
2CompletedTreatmentColorectal Cancers / Lung Cancer Non-Small Cell Cancer (NSCLC)1
2CompletedTreatmentEndometrial Cancers / Second-line Treatment / Solid Tumors and Advanced Endometrial Cancer / VEGF1
2CompletedTreatmentGastrointestinal Stromal Tumors2
2CompletedTreatmentHepatocellular,Carcinoma1
2CompletedTreatmentMalignant Neoplasm of Stomach1
2CompletedTreatmentThyroid Cancers1
2CompletedTreatmentTumor Pathway Activations Inhibited by Dovitinib1
2TerminatedTreatmentAdvanced Malignant Pleural Mesothelioma / MPM1
2TerminatedTreatmentBladder Cancers1
2TerminatedTreatmentColorectal Cancers / Malignant Neoplasm of Pancreas1
2TerminatedTreatmentMetastatic Breast Cancer (MBC)1
2TerminatedTreatmentProstate Cancer1
2TerminatedTreatmentVon Hippel-Lindau Syndrome1
2Unknown StatusTreatmentClear Cell Renal Cell Carcinoma1
2Unknown StatusTreatmentHormone Refractory Prostate Cancer1
2Unknown StatusTreatmentSquamous NSCLC1
2WithdrawnTreatmentGastrinoma / Glucagonoma / Insulinoma / Pancreatic Polypeptide Tumor / Recurrent Islet Cell Carcinoma / Somatostatinoma1
2WithdrawnTreatmentProstate Cancer1
2, 3CompletedTreatmentTumors, Solid1
3CompletedTreatmentMetastatic Renal Cell Carcinoma1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.137 mg/mLALOGPS
logP2.34ALOGPS
logP1.35ChemAxon
logS-3.5ALOGPS
pKa (Strongest Acidic)8.56ChemAxon
pKa (Strongest Basic)7.87ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area90.28 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity112.36 m3·mol-1ChemAxon
Polarizability42.46 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

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

Taxonomy

Description
This compound belongs to the class of organic compounds known as n-arylpiperazines. These are organic compounds containing a piperazine ring where the nitrogen ring atom carries an aryl group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazinanes
Sub Class
Piperazines
Direct Parent
N-arylpiperazines
Alternative Parents
4-aminoquinolines / Haloquinolines / Hydroquinolones / Hydroquinolines / Benzimidazoles / Dialkylarylamines / Aminopyridines and derivatives / N-methylpiperazines / Pyridinones / Aryl fluorides
show 12 more
Substituents
N-arylpiperazine / Aminoquinoline / 4-aminoquinoline / Haloquinoline / Dihydroquinolone / Dihydroquinoline / Quinoline / Benzimidazole / Tertiary aliphatic/aromatic amine / Dialkylarylamine
show 27 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Suppressor
General Function
Zinc ion binding
Specific Function
Nuclear receptor that binds and is activated by variety of endogenous and xenobiotic compounds. Transcription factor that activates the transcription of multiple genes involved in the metabolism an...
Gene Name
NR1I2
Uniprot ID
O75469
Uniprot Name
Nuclear receptor subfamily 1 group I member 2
Molecular Weight
49761.245 Da
References
  1. Weiss J, Theile D, Dvorak Z, Haefeli WE: Interaction potential of the multitargeted receptor tyrosine kinase inhibitor dovitinib with drug transporters and drug metabolising enzymes assessed in vitro. Pharmaceutics. 2014 Dec 16;6(4):632-50. doi: 10.3390/pharmaceutics6040632. [PubMed:25521244]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Vitamin d 24-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
CYP1A1
Uniprot ID
P04798
Uniprot Name
Cytochrome P450 1A1
Molecular Weight
58164.815 Da
References
  1. Weiss J, Theile D, Dvorak Z, Haefeli WE: Interaction potential of the multitargeted receptor tyrosine kinase inhibitor dovitinib with drug transporters and drug metabolising enzymes assessed in vitro. Pharmaceutics. 2014 Dec 16;6(4):632-50. doi: 10.3390/pharmaceutics6040632. [PubMed:25521244]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
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
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Weiss J, Theile D, Dvorak Z, Haefeli WE: Interaction potential of the multitargeted receptor tyrosine kinase inhibitor dovitinib with drug transporters and drug metabolising enzymes assessed in vitro. Pharmaceutics. 2014 Dec 16;6(4):632-50. doi: 10.3390/pharmaceutics6040632. [PubMed:25521244]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Retinoic acid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. Isoform 2 lacks transferase activity but acts as a negative reg...
Gene Name
UGT1A3
Uniprot ID
P35503
Uniprot Name
UDP-glucuronosyltransferase 1-3
Molecular Weight
60337.835 Da
References
  1. Weiss J, Theile D, Dvorak Z, Haefeli WE: Interaction potential of the multitargeted receptor tyrosine kinase inhibitor dovitinib with drug transporters and drug metabolising enzymes assessed in vitro. Pharmaceutics. 2014 Dec 16;6(4):632-50. doi: 10.3390/pharmaceutics6040632. [PubMed:25521244]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Glucuronosyltransferase activity
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds.Its unique specificity for 3,4-catechol estrogens and estriol su...
Gene Name
UGT2B7
Uniprot ID
P16662
Uniprot Name
UDP-glucuronosyltransferase 2B7
Molecular Weight
60694.12 Da
References
  1. Weiss J, Theile D, Dvorak Z, Haefeli WE: Interaction potential of the multitargeted receptor tyrosine kinase inhibitor dovitinib with drug transporters and drug metabolising enzymes assessed in vitro. Pharmaceutics. 2014 Dec 16;6(4):632-50. doi: 10.3390/pharmaceutics6040632. [PubMed:25521244]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. Weiss J, Theile D, Dvorak Z, Haefeli WE: Interaction potential of the multitargeted receptor tyrosine kinase inhibitor dovitinib with drug transporters and drug metabolising enzymes assessed in vitro. Pharmaceutics. 2014 Dec 16;6(4):632-50. doi: 10.3390/pharmaceutics6040632. [PubMed:25521244]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
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
References
  1. Weiss J, Theile D, Dvorak Z, Haefeli WE: Interaction potential of the multitargeted receptor tyrosine kinase inhibitor dovitinib with drug transporters and drug metabolising enzymes assessed in vitro. Pharmaceutics. 2014 Dec 16;6(4):632-50. doi: 10.3390/pharmaceutics6040632. [PubMed:25521244]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Organic anion transmembrane transporter activity
Specific Function
May act as an inducible transporter in the biliary and intestinal excretion of organic anions. Acts as an alternative route for the export of bile acids and glucuronides from cholestatic hepatocyte...
Gene Name
ABCC3
Uniprot ID
O15438
Uniprot Name
Canalicular multispecific organic anion transporter 2
Molecular Weight
169341.14 Da
References
  1. Weiss J, Theile D, Dvorak Z, Haefeli WE: Interaction potential of the multitargeted receptor tyrosine kinase inhibitor dovitinib with drug transporters and drug metabolising enzymes assessed in vitro. Pharmaceutics. 2014 Dec 16;6(4):632-50. doi: 10.3390/pharmaceutics6040632. [PubMed:25521244]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
Inducer
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
References
  1. Weiss J, Theile D, Dvorak Z, Haefeli WE: Interaction potential of the multitargeted receptor tyrosine kinase inhibitor dovitinib with drug transporters and drug metabolising enzymes assessed in vitro. Pharmaceutics. 2014 Dec 16;6(4):632-50. doi: 10.3390/pharmaceutics6040632. [PubMed:25521244]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
References
  1. Weiss J, Theile D, Dvorak Z, Haefeli WE: Interaction potential of the multitargeted receptor tyrosine kinase inhibitor dovitinib with drug transporters and drug metabolising enzymes assessed in vitro. Pharmaceutics. 2014 Dec 16;6(4):632-50. doi: 10.3390/pharmaceutics6040632. [PubMed:25521244]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent transport of organic anions such as taurocholate, the prostaglandins PGD2, PGE1, PGE2, leukotriene C4, thromboxane B2 and iloprost.
Gene Name
SLCO2B1
Uniprot ID
O94956
Uniprot Name
Solute carrier organic anion transporter family member 2B1
Molecular Weight
76709.98 Da
References
  1. Weiss J, Theile D, Dvorak Z, Haefeli WE: Interaction potential of the multitargeted receptor tyrosine kinase inhibitor dovitinib with drug transporters and drug metabolising enzymes assessed in vitro. Pharmaceutics. 2014 Dec 16;6(4):632-50. doi: 10.3390/pharmaceutics6040632. [PubMed:25521244]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
Gene Name
SLCO1B3
Uniprot ID
Q9NPD5
Uniprot Name
Solute carrier organic anion transporter family member 1B3
Molecular Weight
77402.175 Da
References
  1. Weiss J, Theile D, Dvorak Z, Haefeli WE: Interaction potential of the multitargeted receptor tyrosine kinase inhibitor dovitinib with drug transporters and drug metabolising enzymes assessed in vitro. Pharmaceutics. 2014 Dec 16;6(4):632-50. doi: 10.3390/pharmaceutics6040632. [PubMed:25521244]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
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
References
  1. Weiss J, Theile D, Dvorak Z, Haefeli WE: Interaction potential of the multitargeted receptor tyrosine kinase inhibitor dovitinib with drug transporters and drug metabolising enzymes assessed in vitro. Pharmaceutics. 2014 Dec 16;6(4):632-50. doi: 10.3390/pharmaceutics6040632. [PubMed:25521244]

Drug created on November 18, 2007 11:28 / Updated on August 08, 2018 12:11