VEMURAFENIB

Details

Stereochemistry	ACHIRAL
Molecular Formula	C23H18ClF2N3O3S
Molecular Weight	489.922
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CCCS(=O)(=O)NC1=C(F)C(C(=O)C2=CNC3=C2C=C(C=N3)C4=CC=C(Cl)C=C4)=C(F)C=C1

InChI

InChIKey=GPXBXXGIAQBQNI-UHFFFAOYSA-N

InChI=1S/C23H18ClF2N3O3S/c1-2-9-33(31,32)29-19-8-7-18(25)20(21(19)26)22(30)17-12-28-23-16(17)10-14(11-27-23)13-3-5-15(24)6-4-13/h3-8,10-12,29H,2,9H2,1H3,(H,27,28)

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Description

Vemurafenib (trade name Zelboraf) is a low molecular weight, orally available kinase inhibitor. It inhibits of some mutated forms of BRAF serinethreonine kinase, including BRAF V600E and is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. Vemurafenib also inhibits other kinases in vitro such as CRAF, ARAF, wild-type BRAF, SRMS, ACK1, MAP4K5 and FGR at similar concentrations. Vemurafenib is not recommended for use in patients with wild-type BRAF melanoma. Zelboraf does not cure melanoma, but stops it's progression. Some 26% of patients in clinical trials developed a non melanoma form of skin cancer called cutaneous squamous cell carcinoma, which can usually be removed via relatively simple surgery. Other side effects include joint pain, rash, hair loss, fatigue, nausea, and skin sensitivity to sunlight. Patients taking Zelboraf must avoid sun exposure. It's not yet clear how long Zelboraf can increase melanoma survival.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Serine/threonine-protein kinase B-raf 21	Inhibitor 8,504		31.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Advanced melanoma 4	Secondary		Approved 8,583	ZELBORAF

C_max

Value	Dose	Analyte	Population
52.7 μg/mL	720 mg 2 times / day multiple, oral	VEMURAFENIB plasma	Homo sapiens
35.4 μg/mL	480 mg 2 times / day multiple, oral	VEMURAFENIB plasma	Homo sapiens
4.8 μg/mL	960 mg single, oral	VEMURAFENIB plasma	Homo sapiens
4.4 μg/mL	720 mg single, oral	VEMURAFENIB plasma	Homo sapiens
2.6 μg/mL	480 mg single, oral	VEMURAFENIB plasma	Homo sapiens
1.9 μg/mL	240 mg single, oral	VEMURAFENIB plasma	Homo sapiens
62 μg/mL	960 mg 2 times / day multiple, oral	VEMURAFENIB plasma	Homo sapiens
17.2 μg/mL	240 mg 2 times / day multiple, oral	VEMURAFENIB plasma	Homo sapiens
61.4 μg/mL	960 mg 2 times / day multiple, oral	VEMURAFENIB plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
3127.1 μg × h/mL	720 mg 2 times / day multiple, oral	VEMURAFENIB plasma	Homo sapiens
2243.5 μg × h/mL	480 mg 2 times / day multiple, oral	VEMURAFENIB plasma	Homo sapiens
27 μg × h/mL	960 mg single, oral	VEMURAFENIB plasma	Homo sapiens
21.9 μg × h/mL	720 mg single, oral	VEMURAFENIB plasma	Homo sapiens
13.8 μg × h/mL	480 mg single, oral	VEMURAFENIB plasma	Homo sapiens
8.3 μg × h/mL	240 mg single, oral	VEMURAFENIB plasma	Homo sapiens
601 μg × h/mL	960 mg 2 times / day multiple, oral	VEMURAFENIB plasma	Homo sapiens
920.3 μg × h/mL	240 mg 2 times / day multiple, oral	VEMURAFENIB plasma	Homo sapiens
3530.3 μg × h/mL	960 mg 2 times / day multiple, oral	VEMURAFENIB plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
34.9 h	720 mg 2 times / day multiple, oral	VEMURAFENIB plasma	Homo sapiens
38.4 h	480 mg 2 times / day multiple, oral	VEMURAFENIB plasma	Homo sapiens
31.5 h	240 mg 2 times / day multiple, oral	VEMURAFENIB plasma	Homo sapiens
34.1 h	960 mg 2 times / day multiple, oral	VEMURAFENIB plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
1%	960 mg 2 times / day multiple, oral		VEMURAFENIB plasma	Homo sapiens

Doses

Show entries

Dose	Population	Adverse events
960 mg 2 times / day multiple, oral Recommended\|MTD	unhealthy, median age was 54 years	Other AEs: Rash, Photosensitivity reaction...
960 mg 2 times / day multiple, oral Recommended\|MTD	unhealthy, median age was 54 years	Disc. AE: Arthralgia, Dysphagia...
960 mg 2 times / day multiple, oral Recommended\|MTD	unhealthy, median age was 54 years	Other AEs: LDH increased, Alkaline phosphatase increased...
960 mg 2 times / day multiple, oral Recommended\|MTD	unhealthy, median age was 54 years	Other AEs: Arthritis, Joint effusion...
960 mg 2 times / day multiple, oral Recommended\|MTD	unhealthy, median age was 54 years	Other AEs: Rash, Keratoacanthoma...

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AEs

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AE	Significance	Dose	Population
Seborrheic keratosis	10%	960 mg 2 times / day multiple, oral Recommended\|MTD	unhealthy, median age was 54 years
Sunburn	10%	960 mg 2 times / day multiple, oral Recommended\|MTD	unhealthy, median age was 54 years
Asthenia	11%	960 mg 2 times / day multiple, oral Recommended\|MTD	unhealthy, median age was 54 years
Constipation	12%	960 mg 2 times / day multiple, oral Recommended\|MTD	unhealthy, median age was 54 years
Myalgia	13%	960 mg 2 times / day multiple, oral Recommended\|MTD	unhealthy, median age was 54 years

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Overview

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

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 2,153 CYP2C19 2,057 P-gp 1,741 OATP1B1 1,079 OATP1B3 961	P-gp 2,052 OATP1B1 503 OATP1B3 435	P-gp 301 CYP1A2 832 CYP2B6 669

Drug as perpetrator

Show entries

Target	Modality	Activity	Clinical evidence
CYP2D6 2,546	inhibitor 4,027	mild [IC50 33.2 uM]	yes (co-administration study)
CYP1A2 2,333	inhibitor 4,027	moderate [IC50 32.5 uM]	yes (co-administration study)
OATP1B1 1,095	inhibitor 4,027	no
OATP1B3 970	inhibitor 4,027	no
CYP2C19 2,141	inhibitor 4,027	yes [IC50 22.5 uM]

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Drug as victim

Show entries

Target	Modality	Activity
OATP1B1 503	substrate 4,014	no
OATP1B3 435	substrate 4,014	no
CYP3A4 1,946	substrate 4,014	yes
P-gp 2,052	substrate 4,014	yes

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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:63637	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:63637
ChemicalBook	CB02550000	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB02550000
ChemicalBook	CB22515128	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB22515128
eMolecules	32176418	https://www.emolecules.com/cgi-bin/more?vid=32176418
MolPort	MolPort-009-200-481	https://www.molport.com/shop/molecule-link/MolPort-009-200-481

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PubMed

Show entries

Title	Date	PubMed
Novel immunotherapeutic agents and small molecule antagonists of signalling kinases for the treatment of metastatic melanoma.	2011 Jul 9	21770473
BRAF inhibitor activity in V600R metastatic melanoma.	2013 Mar	23237741
Perturbation biology nominates upstream-downstream drug combinations in RAF inhibitor resistant melanoma cells.	2015 Aug 18	26284497
Inhibition of RAF Isoforms and Active Dimers by LY3009120 Leads to Anti-tumor Activities in RAS or BRAF Mutant Cancers.	2015 Sep 14	26343583

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Patents

Sample Use Guides

In Vivo Use Guide

960 mg twice daily. Administer ZELBORAF approximately 12 hours apart with or without a meal. Management of symptomatic adverse drug reactions may require dose reduction, treatment interruption, or treatment discontinuation of ZELBORAF. Dose reductions resulting in a dose below 480 mg twice daily are not recommended

Route of Administration: Oral

In Vitro Use Guide

The antitumor effects of vemurafenib against SM1 cells were tested by in vitro MTS cell proliferation assay after 72 hours of treatment. The IC50 of vemurafenib was 14 uM, which is approximately one log higher than the sensitivity of M229 (IC50 of 0.5 uM), a BRAF V600E mutant human melanoma cell line highly sensitive to vemurafenib, and at a similar range as the relatively resistant BRAF V600E mutant human melanoma cell line M233 (IC50 of 15 uM).

Show entries

Name

Type

Language

vemurafenib [INN]

Preferred Name

English

VEMURAFENIB

Official Name

English

RG 7204

Code

English

VEMURAFENIB [ORANGE BOOK]

Common Name

English

ZELBORAF

Brand Name

English

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Classification Tree

Code System

Code

Designated/Approved

FDA ORPHAN DRUG

325310

Designated/Withdrawn

FDA ORPHAN DRUG

444114

Antineoplastic Protein Inhibitor

NCI_THESAURUS

C129825

NEVI AND MELANOMAS

EMA ASSESSMENT REPORTS

ZELBORAF (AUTHORIZED: MELANOMA)

Positive

EU-Orphan Drug

EU/3/17/1846

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Show entries

Code System

Code

Type

Description

IUPHAR

5893

PRIMARY

RXCUI

1147220

PRIMARY

RxNorm

EVMPD

SUB32161

PRIMARY

NDF-RT

N0000185503

PRIMARY

P-Glycoprotein Inhibitors [MoA]

PUBCHEM

42611257

PRIMARY

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ACTIVE MOIETY


					207SMY3FQT

VEMURAFENIB

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