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
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
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 |
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
Sample Use Guides
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 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
Edited
Mon Oct 21 23:11:34 UTC 2019
by
admin
on
Mon Oct 21 23:11:34 UTC 2019
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Record UNII |
8L7891MRB6
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Record Status |
Validated (UNII)
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Record Version |
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WHO-ATC |
L01XE46
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NCI_THESAURUS |
C129825
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FDA ORPHAN DRUG |
411413
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admin on Mon Oct 21 23:11:35 UTC 2019 , Edited by admin on Mon Oct 21 23:11:35 UTC 2019
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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
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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
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1269440-17-6
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C98283
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SUB177218
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CHEMBL3301612
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9816
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1269440-17-6
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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
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Related Record | Type | Details | ||
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TRANSPORTER -> INHIBITOR |
IC50
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METABOLIC ENZYME -> INHIBITOR |
IC50
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METABOLIC ENZYME -> INHIBITOR |
IC50
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TARGET -> INHIBITOR |
IC50
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TRANSPORTER -> INHIBITOR |
IC50
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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
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METABOLIC ENZYME -> SUBSTRATE |
MAJOR
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TRANSPORTER -> INHIBITOR |
IC50
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TARGET -> INHIBITOR |
IC50
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METABOLIC ENZYME -> INHIBITOR |
IC50
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METABOLIC ENZYME -> INDUCER |
IC50
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METABOLIC ENZYME -> INHIBITOR |
IC50
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METABOLIC ENZYME -> INDUCER |
IC50
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METABOLIC ENZYME -> SUBSTRATE |
MINOR
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TARGET -> INHIBITOR |
IC50
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TRANSPORTER -> INHIBITOR |
IC50
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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
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METABOLIC ENZYME -> INHIBITOR |
IC50
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BINDER->LIGAND |
Encorafenib is 86% bound to human plasma proteins and binding is not concentrationdependent
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METABOLIC ENZYME -> INHIBITOR |
IC50
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TRANSPORTER -> INHIBITOR |
IC50
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METABOLIC ENZYME -> INHIBITOR |
IC50
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METABOLIC ENZYME -> SUBSTRATE |
MINOR
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TRANSPORTER -> INHIBITOR |
IC50
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TRANSPORTER -> SUBSTRATE |
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METABOLIC ENZYME -> INDUCER |
IC50
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TRANSPORTER -> INHIBITOR |
IC50
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Related Record | Type | Details | ||
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ACTIVE MOIETY |
Name | Property Type | Amount | Referenced Substance | Defining | Parameters | References |
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Volume of Distribution | PHARMACOKINETIC |
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DOSE |
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Biological Half-life | PHARMACOKINETIC |
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DOSE |
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Tmax | PHARMACOKINETIC |
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DOSE |
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