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Details

Stereochemistry ABSOLUTE
Molecular Formula C22H27ClFN7O4S
Molecular Weight 540.011
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of ENCORAFENIB

SMILES

COC(=O)N[C@@H](C)CNC1=NC=CC(=N1)C2=CN(N=C2C3=CC(Cl)=CC(NS(C)(=O)=O)=C3F)C(C)C

InChI

InChIKey=CMJCXYNUCSMDBY-ZDUSSCGKSA-N
InChI=1S/C22H27ClFN7O4S/c1-12(2)31-11-16(17-6-7-25-21(28-17)26-10-13(3)27-22(32)35-4)20(29-31)15-8-14(23)9-18(19(15)24)30-36(5,33)34/h6-9,11-13,30H,10H2,1-5H3,(H,27,32)(H,25,26,28)/t13-/m0/s1

HIDE SMILES / InChI

Molecular Formula C22H27ClFN7O4S
Molecular Weight 540.011
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry
Defined Stereocenters 1 / 1
E/Z Centers 0
Optical Activity UNSPECIFIED

Description

Encorafenib, also known as BRAFTOVI or LGX818, is an orally available mutated BRaf V600E inhibitor with potential antineoplastic activity, which was developed by Novartis. LGX818 possesses selective anti-proliferative and apoptotic activity in cells expressing BRAFV600E. In the A375 (BRAFV600E) human melanoma cell line LGX818 suppresses phospho-ERK (EC50 = 3 nM) leading to potent inhibition of proliferation (EC50 = 4 nM). No significant activity was observed against a panel of 100 kinases (IC50 > 900 nM) and LGX818 did not inhibit proliferation of > 400 cell lines expressing wild-type BRAF. On June 27, 2018, the Food and Drug Administration approved encorafenib and Binimetinib (BRAFTOVI and MEKTOVI, Array BioPharma Inc.) in combination for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test. Encorafenib and binimetinib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared with either drug alone, co-administration of encorafenib and binimetinib result in greater anti-proliferative activity in vitro in BRAF mutation-positive cell lines and greater anti-tumor activity with respect to tumor growth inhibition in BRAF V600E mutant human melanoma xenograft studies in mice. In addition to the above, the combination of encorafenib and binimetinib acted to delay the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared with the administration of either drug alone. Encorafenib is in phase III for Metastatic Colorectal Cancer and in phase II for Relapsed or Refractory Multiple Myeloma.

Originator

Approval Year

PubMed

PubMed

TitleDatePubMed
Personalized Preclinical Trials in BRAF Inhibitor-Resistant Patient-Derived Xenograft Models Identify Second-Line Combination Therapies.
2016 Apr 1
Cutaneous toxicity of a new BRAF inhibitor, LGX818 (encorafenib).
2017 Jan-Feb
Patents

Sample Use Guides

In Vivo Use Guide
Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to the initiation of BRAFTOVI. (2.1) The recommended dose is 450 mg orally once daily in combination with binimetinib. Take BRAFTOVI with or without food.
Route of Administration: Oral
In Vitro Use Guide
In the A375 (BRAFV600E) human melanoma cell line LGX818 (ENCORAFENIB) suppresses phospho-ERK (EC50 = 3 nM) leading to potent inhibition of proliferation (EC50 = 4 nM). No significant activity was observed against a panel of 100 kinases (IC50 > 900 nM) and LGX818 did not inhibit proliferation of > 400 cell lines expressing wild-type BRAF.
Substance Class Chemical
Created
by admin
on Mon Oct 21 23:11:34 UTC 2019
Edited
by admin
on Mon Oct 21 23:11:34 UTC 2019
Record UNII
8L7891MRB6
Record Status Validated (UNII)
Record Version
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Name Type Language
ENCORAFENIB
INN   USAN   WHO-DD  
INN   USAN  
Official Name English
LGX-818
Common Name English
ENCORAFENIB [USAN]
Common Name English
BRAFTOVI
Brand Name English
ENCORAFENIB [INN]
Common Name English
LGX818
Common Name English
NVP-LGX818
Code English
ENCORAFENIB [WHO-DD]
Common Name English
NVP-LGX-818-NXA
Code English
CARBAMIC ACID, N-((1S)-2-((4-(3-(5-CHLORO-2-FLUORO-3-((METHYLSULFONYL)AMINO)PHENYL)-1-(1-METHYLETHYL)-1H-PYRAZOL-4-YL)-2-PYRIMIDINYL)AMINO)-1-METHYLETHYL)-, METHYL ESTER
Common Name English
NVP-LGX818-NXA
Code English
METHYL N-((2S)-1-((4-(3-(5-CHLORO-2-FLUORO-3-(METHANESULFONAMIDO)PHENYL)(-1-(PROPAN-2-YL)-1H-PYRAZOL-4-YL(PYRIMIDIN-2-YL)AMINO)PROPAN-2-YL)CARBAMATE
Systematic Name English
Classification Tree Code System Code
WHO-ATC L01XE46
Created by admin on Mon Oct 21 23:11:35 UTC 2019 , Edited by admin on Mon Oct 21 23:11:35 UTC 2019
NCI_THESAURUS C129825
Created by admin on Mon Oct 21 23:11:35 UTC 2019 , Edited by admin on Mon Oct 21 23:11:35 UTC 2019
FDA ORPHAN DRUG 411413
Created by admin on Mon Oct 21 23:11:35 UTC 2019 , Edited by admin on Mon Oct 21 23:11:35 UTC 2019
FDA ORPHAN DRUG 411613
Created by admin on Mon Oct 21 23:11:35 UTC 2019 , Edited by admin on Mon Oct 21 23:11:35 UTC 2019
NCI_THESAURUS C61074
Created by admin on Mon Oct 21 23:11:35 UTC 2019 , Edited by admin on Mon Oct 21 23:11:35 UTC 2019
Code System Code Type Description
EPA CompTox
1269440-17-6
Created by admin on Mon Oct 21 23:11:35 UTC 2019 , Edited by admin on Mon Oct 21 23:11:35 UTC 2019
PRIMARY
NCI_THESAURUS
C98283
Created by admin on Mon Oct 21 23:11:35 UTC 2019 , Edited by admin on Mon Oct 21 23:11:35 UTC 2019
PRIMARY
EVMPD
SUB177218
Created by admin on Mon Oct 21 23:11:35 UTC 2019 , Edited by admin on Mon Oct 21 23:11:35 UTC 2019
PRIMARY
ChEMBL
CHEMBL3301612
Created by admin on Mon Oct 21 23:11:35 UTC 2019 , Edited by admin on Mon Oct 21 23:11:35 UTC 2019
PRIMARY
INN
9816
Created by admin on Mon Oct 21 23:11:35 UTC 2019 , Edited by admin on Mon Oct 21 23:11:35 UTC 2019
PRIMARY
CAS
1269440-17-6
Created by admin on Mon Oct 21 23:11:35 UTC 2019 , Edited by admin on Mon Oct 21 23:11:35 UTC 2019
PRIMARY
PUBCHEM
50922675
Created by admin on Mon Oct 21 23:11:35 UTC 2019 , Edited by admin on Mon Oct 21 23:11:35 UTC 2019
PRIMARY
Related Record Type Details
TRANSPORTER -> INHIBITOR
IC50
METABOLIC ENZYME -> INHIBITOR
IC50
METABOLIC ENZYME -> INHIBITOR
IC50
TARGET -> INHIBITOR
IC50
TRANSPORTER -> INHIBITOR
IC50
EXCRETED UNCHANGED
Following a single 100 mg oral dose of 14C-encorafenib, 47% of the administered dose (1.8% as unchanged) was recovered in the urine.
URINE
METABOLIC ENZYME -> SUBSTRATE
MAJOR
TRANSPORTER -> INHIBITOR
IC50
TARGET -> INHIBITOR
IC50
METABOLIC ENZYME -> INHIBITOR
IC50
METABOLIC ENZYME -> INDUCER
IC50
METABOLIC ENZYME -> INHIBITOR
IC50
METABOLIC ENZYME -> INDUCER
IC50
METABOLIC ENZYME -> SUBSTRATE
MINOR
TARGET -> INHIBITOR
IC50
TRANSPORTER -> INHIBITOR
IC50
EXCRETED UNCHANGED
Following a single 100 mg oral dose of 14C-encorafenib, 39% of the administered dose (5% as unchanged) was recovered in the feces.
FECAL
METABOLIC ENZYME -> INHIBITOR
IC50
BINDER->LIGAND
Encorafenib is 86% bound to human plasma proteins and binding is not concentrationdependent
METABOLIC ENZYME -> INHIBITOR
IC50
TRANSPORTER -> INHIBITOR
IC50
METABOLIC ENZYME -> INHIBITOR
IC50
METABOLIC ENZYME -> SUBSTRATE
MINOR
TRANSPORTER -> INHIBITOR
IC50
TRANSPORTER -> SUBSTRATE
METABOLIC ENZYME -> INDUCER
IC50
TRANSPORTER -> INHIBITOR
IC50
Related Record Type Details
ACTIVE MOIETY
Name Property Type Amount Referenced Substance Defining Parameters References
Volume of Distribution PHARMACOKINETIC DOSE

Biological Half-life PHARMACOKINETIC DOSE

Tmax PHARMACOKINETIC DOSE