Cabozantinib S-malate

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C28H24FN3O5.C4H6O5
Molecular Weight	635.5931
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

O[C@@H](CC(O)=O)C(O)=O.COC1=CC2=NC=CC(OC3=CC=C(NC(=O)C4(CC4)C(=O)NC5=CC=C(F)C=C5)C=C3)=C2C=C1OC

InChI

InChIKey=HFCFMRYTXDINDK-WNQIDUERSA-N

InChI=1S/C28H24FN3O5.C4H6O5/c1-35-24-15-21-22(16-25(24)36-2)30-14-11-23(21)37-20-9-7-19(8-10-20)32-27(34)28(12-13-28)26(33)31-18-5-3-17(29)4-6-18;5-2(4(8)9)1-3(6)7/h3-11,14-16H,12-13H2,1-2H3,(H,31,33)(H,32,34);2,5H,1H2,(H,6,7)(H,8,9)/t;2-/m.0/s1

HIDE SMILES / InChI

Molecular Formula	C4H6O5
Molecular Weight	134.0874
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	1 / 1
E/Z Centers	0
Optical Activity	UNSPECIFIED

Molecular Formula	C28H24FN3O5
Molecular Weight	501.5057
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description

Cabozantinib (development code name XL184; marketed under the trade name Cometriq) is an orally bioavailable, small molecule receptor tyrosine kinase (RTK) inhibitor with potential antineoplastic activity. Cabozantinib strongly binds to and inhibits several RTKs, which are often overexpressed in a variety of cancer cell types, including hepatocyte growth factor receptor (MET), RET (rearranged during transfection), vascular endothelial growth factor receptor types 1 (VEGFR-1), 2 (VEGFR-2), and 3 (VEGFR-3), mast/stem cell growth factor (KIT), FMS-like tyrosine kinase 3 (FLT-3), TIE-2 (TEK tyrosine kinase, endothelial), tropomyosin-related kinase B (TRKB) and AXL. This may result in an inhibition of both tumor growth and angiogenesis, and eventually lead to tumor regression. Cabozantinib was granted orphan drug status by the U.S. Food and Drug Administration (FDA) in January 2011. It is currently undergoing clinical trials for the treatment of prostate, bladder, ovarian, brain, melanoma, breast, non-small cell lung, pancreatic, hepatocellular and kidney cancers.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Proto-oncogene tyrosine-protein kinase receptor Ret 7	Inhibitor 8,504	5.2 nM [IC50]
Hepatocyte growth factor receptor 56	Inhibitor 8,504	1.3 nM [IC50]
Vascular endothelial growth factor receptor 2 112	Inhibitor 8,504	0.035 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Medullary thyroid cancer, metastatic 4	Primary		Approved 8,583	COMETRIQ
Renal cell carcinoma 33	Primary		Approved 8,583	CABOMETYX

C_max

Value	Dose	Co-administered	Analyte	Population
554 ng/mL	140 mg single, oral		CABOZANTINIB plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
58300 ng × h/mL	140 mg single, oral		CABOZANTINIB plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
112 h	140 mg single, oral		CABOZANTINIB plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
0.3%			CABOZANTINIB plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
250 mg 1 times / day multiple, oral Highest studied dose	unhealthy, median age 56 years	Other AEs: Aspartate aminotransferase increased, Palmar-plantar erythrodysesthesia syndrome...
265 mg 1 times / day multiple, oral Highest studied dose	unhealthy, median age 56 years	Other AEs: Mucositis...
175 mg 1 times / day multiple, oral MTD	unhealthy, median age 56 years
162.5 mg 1 times / day multiple, oral	unhealthy, median age 56 years	Other AEs: Diarrhea, Fatigue...
175 mg 1 times / day multiple, oral	unhealthy, median age 56 years	Other AEs: Pulmonary embolism...

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AEs

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AE	Significance	Dose	Population
Aspartate aminotransferase increased	grade 3, 16.7%	250 mg 1 times / day multiple, oral Highest studied dose	unhealthy, median age 56 years
Palmar-plantar erythrodysesthesia syndrome	grade 3, 16.7%	250 mg 1 times / day multiple, oral Highest studied dose	unhealthy, median age 56 years
Mucositis	grade 2, 20%	265 mg 1 times / day multiple, oral Highest studied dose	unhealthy, median age 56 years
Fatigue	grade 3, 13%	162.5 mg 1 times / day multiple, oral	unhealthy, median age 56 years
Lipase increased	grade 3, 18%	162.5 mg 1 times / day multiple, oral	unhealthy, median age 56 years

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,946 inhibitor 2,252 inducer 1,087	substrate 1,193 inhibitor 2,438 inducer 440	inhibitor 2,507	inhibitor 2,217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C8 1,057 CYP2C19 2,057 P-gp 1,741 BCRP 910 BSEP 550 MRP2 499 OAT1 725 OAT3 747 OCT1 620 OATP1B1 1,079 OATP1B3 961	MRP2 252 OAT1 395 OCT1 393 OATP1B1 503 OATP1B3 435 MATE1 182 MATE2 98 P-gp 2,052	CYP1A1 151 CYP1A2 832 CYP2B6 669 CYP2C8 198 CYP2C19 329

Drug as perpetrator

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Target	Modality	Activity
BCRP 985	inhibitor 4,027	no
BSEP 554	inhibitor 4,027	no
CYP1A2 2,333	inducer 1,966	no
CYP2B6 1,160	inducer 1,966	no
CYP2C19 2,141	inducer 1,966	no

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Drug as victim

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Target	Modality	Activity
OAT1 395	substrate 4,014	no
OATP1B1 503	substrate 4,014	no
OATP1B3 435	substrate 4,014	no
OCT1 393	substrate 4,014	no
P-gp 2,052	substrate 4,014	no

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2,263	inhibitor 2,237

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
ChEBI	CHEBI:72317	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:72317
eMolecules	36516753	https://www.emolecules.com/cgi-bin/more?vid=36516753
MolPort	MolPort-021-804-939	https://www.molport.com/shop/molecule-link/MolPort-021-804-939
Selleck Chemicals	XL184	http://www.selleckchem.com/products/XL184.html
ZINC	ZINC000070466416	http://zinc15.docking.org/substances/ZINC000070466416

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PubMed

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Title	Date	PubMed
Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth.	2011 Dec	21926191

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Patents

Sample Use Guides

In Vivo Use Guide

Recommended Dose: 140 mg orally, once daily

Route of Administration: Oral

In Vitro Use Guide

For in vitro assays, 10 mM cabozantinib stock solutions were prepared in dimethyl sulfoxide (DMSO) and diluted in the appropriate media.

Substance Class	Chemical
Record UNII	DR7ST46X58
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

Cabozantinib S-malate

Official Name

English

CABOMETYX

Preferred Name

English

N-(4-((6,7-DIMETHOXYQUINOLIN-4-YL)OXY)PHENYL)-N'-(4-FLUOROPHENYL)CYCLOPROPANE-1,1-DICARBOXAMIDE MONO((2S)-2-HYDROXYBUTANEDIOATE)

Systematic Name

English

XL-184

Code

English

XL184

Code

English

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Classification Tree

Code System

Code

Protein Kinase Inhibitor

NCI_THESAURUS

C1967

Positive

EU-Orphan Drug

EU/3/08/610

Antineoplastic Agent

NCI_THESAURUS

C1742

Antineoplastic Protein Inhibitor

NCI_THESAURUS

C129825

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Code System

Code

Type

Description

ChEMBL

CHEMBL2105717

PRIMARY

CAS

1140909-48-3

PRIMARY

EVMPD

SUB176318

PRIMARY

DAILYMED

DR7ST46X58

PRIMARY

SMS_ID

100000162458

PRIMARY

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SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator