GOLVATINIB

Details

Stereochemistry	ACHIRAL
Molecular Formula	C33H37F2N7O4
Molecular Weight	633.6882
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CN1CCN(CC1)C2CCN(CC2)C(=O)NC3=NC=CC(OC4=CC=C(NC(=O)C5(CC5)C(=O)NC6=CC=C(F)C=C6)C(F)=C4)=C3

InChI

InChIKey=UQRCJCNVNUFYDX-UHFFFAOYSA-N

InChI=1S/C33H37F2N7O4/c1-40-16-18-41(19-17-40)24-9-14-42(15-10-24)32(45)39-29-21-26(8-13-36-29)46-25-6-7-28(27(35)20-25)38-31(44)33(11-12-33)30(43)37-23-4-2-22(34)3-5-23/h2-8,13,20-21,24H,9-12,14-19H2,1H3,(H,37,43)(H,38,44)(H,36,39,45)

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/25278451 | https://www.ncbi.nlm.nih.gov/pubmed/24371262
Curator's Comment: Description was created based on several sources, including https://www.cancer.gov/publications/dictionaries/cancer-drug?cdrid=640626 https://www.ncbi.nlm.nih.gov/pubmed/19832844

Golvatinib is a highly potent, small-molecule, ATP-competitive inhibitor of c-Met and multiple members of the Eph receptor family plus c-Kit and Ron. Eisai was developing an oral formulation of golvatinib, which acts as both a c-Met inhibitor and a vascular endothelial growth factor receptor 2 antagonist with potential antineoplastic activity. Golvatinib binds to and inhibits the activities of both c-Met and VEGFR-2, which may inhibit tumor cell growth and survival of tumor cells that overexpress these receptor tyrosine kinases. c-Met and VEGFR-2 are upregulated in a variety of various tumor cell types and play important roles in tumor cell growth, migration and angiogenesis. Clinical trials involving several forms of cancer are currently underway.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Hepatocyte growth factor receptor 54 Target ID: CHEMBL3717 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19832844 \| https://www.ncbi.nlm.nih.gov/pubmed/25082515	Inhibitor 8297		20.0 nM [IC50]
Vascular endothelial growth factor receptor 2 104 Target ID: CHEMBL279 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19832844 \| https://www.ncbi.nlm.nih.gov/pubmed/25082515	Antagonist 2778		40.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Hepatocellular carcinoma 83 Sources: https://clinicaltrials.gov/ct2/show/NCT01271504	Primary	Phase II 1132	Unknown Approved Use Unknown
Head and neck squamous cell carcinoma 32 Sources: https://clinicaltrials.gov/ct2/show/NCT01332266	Primary	Phase II 1132	Unknown Approved Use Unknown
Gastric cancer 53 Sources: https://clinicaltrials.gov/ct2/show/NCT01355302	Primary	Phase II 1132	Unknown Approved Use Unknown

AUC

Value	Dose	Co-administered	Analyte	Population
171000 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25278451	400 mg 1 times / day steady-state, oral dose: 400 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		GOLVATINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
45 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25278451	400 mg 1 times / day steady-state, oral dose: 400 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		GOLVATINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

Doses

Dose	Population	Adverse events
450 mg 1 times / day multiple, oral Highest studied dose Dose: 450 mg, 1 times / day Route: oral Route: multiple Dose: 450 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/25278451 Page: p.6287	unhealthy, ADULT n = 2 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 2 Sources: https://pubmed.ncbi.nlm.nih.gov/25278451 Page: p.6287	DLT: Fatigue, Fatigue... Disc. AE: Vomiting... Dose limiting toxicities: Fatigue (grade 2, 50%) Fatigue (grade 3, 50%) AEs leading to discontinuation/dose reduction: Vomiting (50%) Sources: https://pubmed.ncbi.nlm.nih.gov/25278451 Page: p.6287
200 mg 2 times / day multiple, oral MTD Dose: 200 mg, 2 times / day Route: oral Route: multiple Dose: 200 mg, 2 times / day Sources: https://ascopubs.org/doi/abs/10.1200/jco.2012.30.15_suppl.3079	unhealthy, ADULT n = 3 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 3 Sources: https://ascopubs.org/doi/abs/10.1200/jco.2012.30.15_suppl.3079	Sources: https://ascopubs.org/doi/abs/10.1200/jco.2012.30.15_suppl.3079
400 mg 1 times / day multiple, oral MTD Dose: 400 mg, 1 times / day Route: oral Route: multiple Dose: 400 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/25278451 Page: p.6287	unhealthy, ADULT n = 16 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 16 Sources: https://pubmed.ncbi.nlm.nih.gov/25278451 Page: p.6287	Disc. AE: Fatigue, Anorexia... AEs leading to discontinuation/dose reduction: Fatigue (12.5%) Anorexia (12.5%) Sources: https://pubmed.ncbi.nlm.nih.gov/25278451 Page: p.6287
300 mg 2 times / day multiple, oral Studied dose Dose: 300 mg, 2 times / day Route: oral Route: multiple Dose: 300 mg, 2 times / day Sources: https://ascopubs.org/doi/abs/10.1200/jco.2012.30.15_suppl.3079	unhealthy, ADULT n = 2 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 2 Sources: https://ascopubs.org/doi/abs/10.1200/jco.2012.30.15_suppl.3079	DLT: ALT increased... Other AEs: Vomiting, Nausea... Dose limiting toxicities: ALT increased (grade 3, 50%) Other AEs: Vomiting (grade 2, 50%) Nausea (grade 2, 50%) Anorexia (grade 2, 50%) Sources: https://ascopubs.org/doi/abs/10.1200/jco.2012.30.15_suppl.3079

AEs

AE	Significance	Dose	Population
Vomiting	50% Disc. AE	450 mg 1 times / day multiple, oral Highest studied dose Dose: 450 mg, 1 times / day Route: oral Route: multiple Dose: 450 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/25278451 Page: p.6287	unhealthy, ADULT n = 2 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 2 Sources: https://pubmed.ncbi.nlm.nih.gov/25278451 Page: p.6287
Fatigue	grade 2, 50% DLT, Disc. AE	450 mg 1 times / day multiple, oral Highest studied dose Dose: 450 mg, 1 times / day Route: oral Route: multiple Dose: 450 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/25278451 Page: p.6287	unhealthy, ADULT n = 2 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 2 Sources: https://pubmed.ncbi.nlm.nih.gov/25278451 Page: p.6287
Fatigue	grade 3, 50% DLT, Disc. AE	450 mg 1 times / day multiple, oral Highest studied dose Dose: 450 mg, 1 times / day Route: oral Route: multiple Dose: 450 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/25278451 Page: p.6287	unhealthy, ADULT n = 2 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 2 Sources: https://pubmed.ncbi.nlm.nih.gov/25278451 Page: p.6287
Anorexia	12.5% Disc. AE	400 mg 1 times / day multiple, oral MTD Dose: 400 mg, 1 times / day Route: oral Route: multiple Dose: 400 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/25278451 Page: p.6287	unhealthy, ADULT n = 16 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 16 Sources: https://pubmed.ncbi.nlm.nih.gov/25278451 Page: p.6287
Fatigue	12.5% Disc. AE	400 mg 1 times / day multiple, oral MTD Dose: 400 mg, 1 times / day Route: oral Route: multiple Dose: 400 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/25278451 Page: p.6287	unhealthy, ADULT n = 16 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 16 Sources: https://pubmed.ncbi.nlm.nih.gov/25278451 Page: p.6287
Anorexia	grade 2, 50%	300 mg 2 times / day multiple, oral Studied dose Dose: 300 mg, 2 times / day Route: oral Route: multiple Dose: 300 mg, 2 times / day Sources: https://ascopubs.org/doi/abs/10.1200/jco.2012.30.15_suppl.3079	unhealthy, ADULT n = 2 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 2 Sources: https://ascopubs.org/doi/abs/10.1200/jco.2012.30.15_suppl.3079
Nausea	grade 2, 50%	300 mg 2 times / day multiple, oral Studied dose Dose: 300 mg, 2 times / day Route: oral Route: multiple Dose: 300 mg, 2 times / day Sources: https://ascopubs.org/doi/abs/10.1200/jco.2012.30.15_suppl.3079	unhealthy, ADULT n = 2 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 2 Sources: https://ascopubs.org/doi/abs/10.1200/jco.2012.30.15_suppl.3079
Vomiting	grade 2, 50%	300 mg 2 times / day multiple, oral Studied dose Dose: 300 mg, 2 times / day Route: oral Route: multiple Dose: 300 mg, 2 times / day Sources: https://ascopubs.org/doi/abs/10.1200/jco.2012.30.15_suppl.3079	unhealthy, ADULT n = 2 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 2 Sources: https://ascopubs.org/doi/abs/10.1200/jco.2012.30.15_suppl.3079
ALT increased	grade 3, 50% DLT	300 mg 2 times / day multiple, oral Studied dose Dose: 300 mg, 2 times / day Route: oral Route: multiple Dose: 300 mg, 2 times / day Sources: https://ascopubs.org/doi/abs/10.1200/jco.2012.30.15_suppl.3079	unhealthy, ADULT n = 2 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 2 Sources: https://ascopubs.org/doi/abs/10.1200/jco.2012.30.15_suppl.3079

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587	inhibitor 1767	inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1461

Drug as perpetrator

Target	Modality	Activity
CYP2C9 1819	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645842#sid=363680153	inconclusive [IC50 21.3174 uM]
P-gp 1650	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=363680153	inconclusive [IC50 25.929 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645840#sid=363680153	inconclusive [IC50 6.7412 uM]
CYP3A4 1925	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645841#sid=363680153	yes [IC50 26.837 uM]

PubMed

Title	Date	PubMed
		252160604
E7050: a dual c-Met and VEGFR-2 tyrosine kinase inhibitor promotes tumor regression and prolongs survival in mouse xenograft models.	2010 Jan	19832844
Paracrine receptor activation by microenvironment triggers bypass survival signals and ALK inhibitor resistance in EML4-ALK lung cancer cells.	2012 Jul 1	22553343

Patents

Sample Use Guides

In Vivo Use Guide

Golvatinib at the MTD of 400 mg once daily was well tolerated with pharmacodynamic evidence of c-Met target modulation.

Route of Administration: Oral

In Vitro Use Guide

Golvatinib strongly inhibits the growth of MKN45, EBC-1, Hs746T, and SNU-5 tumor cells with IC50 values of 37, 6.2, 23, and 24 nM, respectively

Name

Type

Language

GOLVATINIB

Official Name

English

GOLVATINIB [USAN]

Common Name

English

E-7050

Code

English

1,1-CYCLOPROPANEDICARBOXAMIDE, N-(2-FLUORO-4-((2-(((4-(4-METHYL-1-PIPERAZINYL)-1-PIPERIDINYL)CARBONYL)AMINO)-4-PYRIDINYL)OXY)PHENYL)-N'-(4-FLUOROPHENYL)-

Systematic Name

English

Golvatinib [WHO-DD]

Common Name

English

E7050

Code

English

golvatinib [INN]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C129825