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Details

Stereochemistry ACHIRAL
Molecular Formula C21H21FN6O
Molecular Weight 392.4302
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of DOVITINIB

SMILES

CN1CCN(CC1)c2ccc3c(c2)[nH]c(-c4c(c5c(cccc5nc4O)F)N)n3

InChI

InChIKey=PIQCTGMSNWUMAF-UHFFFAOYSA-N
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)

HIDE SMILES / InChI

Molecular Formula C21H21FN6O
Molecular Weight 392.4302
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

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.

Approval Year

TargetsConditions

Conditions

Doses

Doses

DosePopulationAdverse 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%)
Alanine aminotransferase increased (grade 3-4, 16.7%)
AEs leading to
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%)
Anorexia (grade 3, 33.3%)
Fatigue (grade 3, 33.3%)
Sources: Page: p.2078
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%)
Neutropenia (grade 3-4, 25%)
Other AEs:
WBC decreased (grade 3-4, 25%)
Neutropenia (grade 3-4, 50%)
Neutropenia (grade 3-4, 25%)
Sources:
AEs

AEs

AESignificanceDosePopulation
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:
OverviewDrug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
no [IC50 ~363 uM]
no
no
no
no
no
no
no
no
no
no
no
weak [IC50 105.2 uM]
weak [IC50 76.5 uM]
weak [Inhibition 20 uM]
weak [Inhibition 20 uM]
yes [EC50 0.609 uM]
yes [IC50 10.3 uM]
yes
yes
yes
yes
yes
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
major
minor
minor
minor
yes (co-administration study)
Comment: Fluvoxamine increased Cmax and AUC(0-72h) by 80% and 188%.
Sourcing

Sourcing

Vendor/AggregatorIDURL
PubMed

PubMed

TitleDatePubMed
CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma.
2005 Apr 1
Design, structure-activity relationships and in vivo characterization of 4-amino-3-benzimidazol-2-ylhydroquinolin-2-ones: a novel class of receptor tyrosine kinase inhibitors.
2009 Jan 22
Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry.
2010 Nov 24
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

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
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.
Substance Class Chemical
Created
by admin
on Sat Jun 26 05:51:11 UTC 2021
Edited
by admin
on Sat Jun 26 05:51:11 UTC 2021
Record UNII
I35H55G906
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
DOVITINIB
INN   WHO-DD  
INN  
Official Name English
TKI-258
Code English
GFKI-258
Code English
4-AMINO-5-FLUORO-3-(6-(4-METHYLPIPERAZIN-1-YL)-1H-BENZIMIDAZOL-2-YL)QUINOLIN-2(1H)-ONE
Systematic Name English
DOVITINIB [INN]
Common Name English
DOVITINIB [WHO-DD]
Common Name English
Classification Tree Code System Code
NCI_THESAURUS C129825
Created by admin on Sat Jun 26 05:51:11 UTC 2021 , Edited by admin on Sat Jun 26 05:51:11 UTC 2021
NCI_THESAURUS C1967
Created by admin on Sat Jun 26 05:51:11 UTC 2021 , Edited by admin on Sat Jun 26 05:51:11 UTC 2021
FDA ORPHAN DRUG 388012
Created by admin on Sat Jun 26 05:51:11 UTC 2021 , Edited by admin on Sat Jun 26 05:51:11 UTC 2021
FDA ORPHAN DRUG 210105
Created by admin on Sat Jun 26 05:51:11 UTC 2021 , Edited by admin on Sat Jun 26 05:51:11 UTC 2021
Code System Code Type Description
EVMPD
SUB177210
Created by admin on Sat Jun 26 05:51:11 UTC 2021 , Edited by admin on Sat Jun 26 05:51:11 UTC 2021
PRIMARY
PUBCHEM
135398510
Created by admin on Sat Jun 26 05:51:11 UTC 2021 , Edited by admin on Sat Jun 26 05:51:11 UTC 2021
PRIMARY
ChEMBL
CHEMBL522892
Created by admin on Sat Jun 26 05:51:11 UTC 2021 , Edited by admin on Sat Jun 26 05:51:11 UTC 2021
PRIMARY
DRUG BANK
DB05928
Created by admin on Sat Jun 26 05:51:11 UTC 2021 , Edited by admin on Sat Jun 26 05:51:11 UTC 2021
PRIMARY
INN
8847
Created by admin on Sat Jun 26 05:51:11 UTC 2021 , Edited by admin on Sat Jun 26 05:51:11 UTC 2021
PRIMARY
CAS
405169-16-6
Created by admin on Sat Jun 26 05:51:11 UTC 2021 , Edited by admin on Sat Jun 26 05:51:11 UTC 2021
PRIMARY
NCI_THESAURUS
C76199
Created by admin on Sat Jun 26 05:51:11 UTC 2021 , Edited by admin on Sat Jun 26 05:51:11 UTC 2021
PRIMARY
FDA UNII
I35H55G906
Created by admin on Sat Jun 26 05:51:11 UTC 2021 , Edited by admin on Sat Jun 26 05:51:11 UTC 2021
PRIMARY
Related Record Type Details
TARGET -> INHIBITOR
TARGET -> INHIBITOR
TARGET -> INHIBITOR
TARGET -> INHIBITOR
INHIBITOR
Related Record Type Details
ACTIVE MOIETY