Details
Stereochemistry | RACEMIC |
Molecular Formula | C21H21FN6O.C3H6O3.H2O |
Molecular Weight | 500.5227 |
Optical Activity | ( + / - ) |
Defined Stereocenters | 0 / 1 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
O.CC(O)C(O)=O.CN1CCN(CC1)C2=CC3=C(C=C2)N=C(N3)C4=C(N)C5=C(NC4=O)C=CC=C5F
InChI
InChIKey=QDPVYZNVVQQULH-UHFFFAOYSA-N
InChI=1S/C21H21FN6O.C3H6O3.H2O/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;1-2(4)3(5)6;/h2-6,11H,7-10H2,1H3,(H,24,25)(H3,23,26,29);2,4H,1H3,(H,5,6);1H2
Dovitinib is an orally active small molecule that exhibits potent inhibitory activity against multiple receptor tyrosine kinases (RTK) involved in tumor growth and angiogenesis. Dovitinib strongly binds to fibroblast growth factor receptor 3 (FGFR3) and inhibits its phosphorylation, which may result in the inhibition of tumor cell proliferation and the induction of tumor cell death. In addition, this agent may inhibit other members of the RTK superfamily, including the vascular endothelial growth factor receptor; fibroblast growth factor receptor 1; platelet-derived growth factor receptor type 3; FMS-like tyrosine kinase 3; stem cell factor receptor (c-KIT); and colony-stimulating factor receptor 1; this may result in an additional reduction in cellular proliferation and angiogenesis, and the induction of tumor cell apoptosis. There are several ongoing Phase I/III clinical trials for dovitinib.
CNS Activity
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL1974 Sources: https://www.drugbank.ca/drugs/DB05928 |
0.001 µM [IC50] | ||
Target ID: CHEMBL1936 Sources: https://www.drugbank.ca/drugs/DB05928 |
0.002 µM [IC50] | ||
Target ID: CHEMBL1844 Sources: https://www.drugbank.ca/drugs/DB05928 |
0.036 µM [IC50] | ||
Target ID: CHEMBL3650 Sources: https://www.drugbank.ca/drugs/DB05928 |
0.008 µM [IC50] | ||
Target ID: CHEMBL2742 Sources: https://www.drugbank.ca/drugs/DB05928 |
0.009 µM [IC50] | ||
Target ID: CHEMBL1868 Sources: https://www.drugbank.ca/drugs/DB05928 |
0.01 µM [IC50] | ||
Target ID: CHEMBL279 Sources: https://www.drugbank.ca/drugs/DB05928 |
0.013 µM [IC50] | ||
Target ID: CHEMBL1955 Sources: https://www.drugbank.ca/drugs/DB05928 |
0.008 µM [IC50] | ||
Target ID: CHEMBL2007 Sources: https://www.drugbank.ca/drugs/DB05928 |
0.21 µM [IC50] | ||
Target ID: CHEMBL1913 Sources: https://www.drugbank.ca/drugs/DB05928 |
0.027 µM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | DOVITINIB Approved UseUnknown |
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Primary | DOVITINIB Approved UseUnknown |
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Primary | DOVITINIB Approved UseUnknown |
|||
Primary | DOVITINIB Approved UseUnknown |
|||
Primary | DOVITINIB Approved UseUnknown |
Doses
Dose | Population | Adverse events |
---|---|---|
125 mg 1 times / day multiple, oral MTD Dose: 125 mg, 1 times / day Route: oral Route: multiple Dose: 125 mg, 1 times / day Sources: Page: p.2078 |
unhealthy, ADULT n = 7 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 7 Sources: Page: p.2078 |
|
500 mg 1 times / day multiple, oral MTD Dose: 500 mg, 1 times / day Route: oral Route: multiple Dose: 500 mg, 1 times / day Sources: Page: p.6 |
unhealthy, ADULT n = 6 Health Status: unhealthy Condition: glioblastoma Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: Page: p.6 |
DLT: Thrombocytopenia, Alanine aminotransferase increased... Disc. AE: Deep vein thrombosis... Other AEs: GGT increased... Dose limiting toxicities: Thrombocytopenia (grade 3-4, 16.7%) AEs leading toAlanine aminotransferase increased (grade 3-4, 16.7%) discontinuation/dose reduction: Deep vein thrombosis (grade 3-4, 16.7%) Other AEs:GGT increased (16.7%) Sources: Page: p.6 |
300 mg 1 times / day multiple, oral RP2D Dose: 300 mg, 1 times / day Route: oral Route: multiple Dose: 300 mg, 1 times / day Sources: Page: p.6 |
unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: Page: p.6 |
Other AEs: Alanine aminotransferase increase... Other AEs: Alanine aminotransferase increase (grade 3-4) Sources: Page: p.6 |
175 mg 1 times / day multiple, oral Studied dose Dose: 175 mg, 1 times / day Route: oral Route: multiple Dose: 175 mg, 1 times / day Sources: Page: p.2078 |
unhealthy, ADULT n = 3 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 3 Sources: Page: p.2078 |
DLT: Alkaline phosphatase serum increased, Anorexia... Dose limiting toxicities: Alkaline phosphatase serum increased (grade 3, 33.3%) Sources: Page: p.2078Anorexia (grade 3, 33.3%) Fatigue (grade 3, 33.3%) |
400 mg 1 times / day multiple, oral Studied dose Dose: 400 mg, 1 times / day Route: oral Route: multiple Dose: 400 mg, 1 times / day Sources: |
unhealthy, ADULT n = 4 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 4 Sources: |
DLT: Alanine aminotransferase increased, Neutropenia... Other AEs: WBC decreased, Neutropenia... Dose limiting toxicities: Alanine aminotransferase increased (grade 3-4, 25%) Other AEs:Neutropenia (grade 3-4, 25%) WBC decreased (grade 3-4, 25%) Sources: Neutropenia (grade 3-4, 50%) Neutropenia (grade 3-4, 25%) |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
GGT increased | 16.7% | 500 mg 1 times / day multiple, oral MTD Dose: 500 mg, 1 times / day Route: oral Route: multiple Dose: 500 mg, 1 times / day Sources: Page: p.6 |
unhealthy, ADULT n = 6 Health Status: unhealthy Condition: glioblastoma Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: Page: p.6 |
Alanine aminotransferase increased | grade 3-4, 16.7% DLT |
500 mg 1 times / day multiple, oral MTD Dose: 500 mg, 1 times / day Route: oral Route: multiple Dose: 500 mg, 1 times / day Sources: Page: p.6 |
unhealthy, ADULT n = 6 Health Status: unhealthy Condition: glioblastoma Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: Page: p.6 |
Thrombocytopenia | grade 3-4, 16.7% DLT |
500 mg 1 times / day multiple, oral MTD Dose: 500 mg, 1 times / day Route: oral Route: multiple Dose: 500 mg, 1 times / day Sources: Page: p.6 |
unhealthy, ADULT n = 6 Health Status: unhealthy Condition: glioblastoma Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: Page: p.6 |
Deep vein thrombosis | grade 3-4, 16.7% Disc. AE |
500 mg 1 times / day multiple, oral MTD Dose: 500 mg, 1 times / day Route: oral Route: multiple Dose: 500 mg, 1 times / day Sources: Page: p.6 |
unhealthy, ADULT n = 6 Health Status: unhealthy Condition: glioblastoma Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: Page: p.6 |
Alanine aminotransferase increase | grade 3-4 | 300 mg 1 times / day multiple, oral RP2D Dose: 300 mg, 1 times / day Route: oral Route: multiple Dose: 300 mg, 1 times / day Sources: Page: p.6 |
unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: Page: p.6 |
Anorexia | grade 3, 33.3% DLT |
175 mg 1 times / day multiple, oral Studied dose Dose: 175 mg, 1 times / day Route: oral Route: multiple Dose: 175 mg, 1 times / day Sources: Page: p.2078 |
unhealthy, ADULT n = 3 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 3 Sources: Page: p.2078 |
Fatigue | grade 3, 33.3% DLT |
175 mg 1 times / day multiple, oral Studied dose Dose: 175 mg, 1 times / day Route: oral Route: multiple Dose: 175 mg, 1 times / day Sources: Page: p.2078 |
unhealthy, ADULT n = 3 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 3 Sources: Page: p.2078 |
Alkaline phosphatase serum increased | grade 3, 33.3% DLT, Disc. AE |
175 mg 1 times / day multiple, oral Studied dose Dose: 175 mg, 1 times / day Route: oral Route: multiple Dose: 175 mg, 1 times / day Sources: Page: p.2078 |
unhealthy, ADULT n = 3 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 3 Sources: Page: p.2078 |
Neutropenia | grade 3-4, 25% | 400 mg 1 times / day multiple, oral Studied dose Dose: 400 mg, 1 times / day Route: oral Route: multiple Dose: 400 mg, 1 times / day Sources: |
unhealthy, ADULT n = 4 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 4 Sources: |
WBC decreased | grade 3-4, 25% | 400 mg 1 times / day multiple, oral Studied dose Dose: 400 mg, 1 times / day Route: oral Route: multiple Dose: 400 mg, 1 times / day Sources: |
unhealthy, ADULT n = 4 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 4 Sources: |
Alanine aminotransferase increased | grade 3-4, 25% DLT |
400 mg 1 times / day multiple, oral Studied dose Dose: 400 mg, 1 times / day Route: oral Route: multiple Dose: 400 mg, 1 times / day Sources: |
unhealthy, ADULT n = 4 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 4 Sources: |
Neutropenia | grade 3-4, 25% DLT |
400 mg 1 times / day multiple, oral Studied dose Dose: 400 mg, 1 times / day Route: oral Route: multiple Dose: 400 mg, 1 times / day Sources: |
unhealthy, ADULT n = 4 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 4 Sources: |
Neutropenia | grade 3-4, 50% | 400 mg 1 times / day multiple, oral Studied dose Dose: 400 mg, 1 times / day Route: oral Route: multiple Dose: 400 mg, 1 times / day Sources: |
unhealthy, ADULT n = 4 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 4 Sources: |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
Drug as perpetrator
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
major | ||||
minor | ||||
minor | ||||
minor | yes (co-administration study) Comment: Fluvoxamine increased Cmax and AUC(0-72h) by 80% and 188%. Sources: https://pubmed.ncbi.nlm.nih.gov/29101463/ |
PubMed
Title | Date | PubMed |
---|---|---|
CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma. | 2005 Apr 1 |
|
Comprehensive analysis of kinase inhibitor selectivity. | 2011 Oct 30 |
|
Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. | 2011 Oct 30 |
|
A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. | 2013 Apr 15 |
Patents
Sample Use Guides
Patients received 500 mg of dovitinib taken orally on 5 days on/2 days off dosing schedule.
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/15598814
Dovitinib (CHIR-258) inhibited members of the class III receptor tyrosine kinases (RTK) including FLT3, c-Kit, CSF-1R, and PDGFRa/b with IC50 values of 0.001 to 0.21 mM as assessed by in vitro kinase assays. In addition, CHIR-258 potently inhibited class IV (FGFR1 and 3) and class V (VEGFR1-4) RTKs with IC50 values of 0.008 to 0.013 mM. For insulin receptor, EGFR, c-Met, EphrinA2, Tie2, IGFR1, and HER2 significant inhibition was observed only at more than 10-fold higher concentrations. These studies demonstrated that CHIR-258 is a selective but multitargeted inhibitor of class III, IV, and V RTKs with high potency against FGFRs.
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Classification Tree | Code System | Code | ||
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NCI_THESAURUS |
C1967
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NCI_THESAURUS |
C129825
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Code System | Code | Type | Description | ||
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DBSALT002512
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SS-55
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915769-50-5
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CHEMBL522892
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69VKY8P7EA
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100000128324
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135611162
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C62435
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SUB35226
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ACTIVE MOIETY
PARENT (SALT/SOLVATE)
SUBSTANCE RECORD