Encorafenib

Identification

Summary

Encorafenib is a kinase inhibitor used to treat unresectable or metastatic melanoma with specific mutations.

Brand Names
Braftovi
Generic Name
Encorafenib
DrugBank Accession Number
DB11718
Background

Encorafenib, also known as BRAFTOVI, is a kinase inhibitor. Encorafenib inhibits BRAF gene, which encodes for B-raf protein, which is a proto-oncogene involved in various genetic mutations.4 This protein plays a role in regulating the MAP kinase/ERK signaling pathway, which impacts cell division, differentiation, and secretion. Mutations in this gene, most frequently the V600E mutation, are the most commonly identified cancer-causing mutations in melanoma, and have been isolated in various other cancers as well, including non-Hodgkin lymphoma, colorectal cancer, thyroid carcinoma, non-small cell lung carcinoma, hairy cell leukemia and adenocarcinoma of the lung.2

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.4

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 540.01
Monoisotopic: 539.1517794
Chemical Formula
C22H27ClFN7O4S
Synonyms
  • Encorafenib
External IDs
  • LGX-818
  • LGX818
  • NVP-LGX-818-NXA
  • NVP-LGX818
  • NVP-LGX818-NXA

Pharmacology

Indication

Encorafenib is indicated in combination with binimetinib for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation and metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation. It is also indicated in combination with cetuximab for the treatment of adult patients with metastatic colorectal cancer with a BRAF V600E mutation.5

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used in combination to treatMetastatic colorectal cancer (crc)Regimen in combination with: Cetuximab (DB00002)••••••••••••••••••••••••
Used in combination to treatMetastatic melanomaRegimen in combination with: Binimetinib (DB11967)•••••••••••••••••••
Used in combination to treatMetastatic melanomaRegimen in combination with: Binimetinib (DB11967)•••••••••••••••••••
Used in combination to treatMetastatic non-small cell lung cancerRegimen in combination with: Binimetinib (DB11967)••••••••••••••••••••••••
Used in combination to treatUnresectable melanomaRegimen in combination with: Binimetinib (DB11967)•••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Encorafenib has a pharmacologic profile that is distinct from that of other clinically active BRAF inhibitors and has shown improved efficacy in the treatment of metastatic melanoma.3,1

Once-daily dosing of single-agent encorafenib has a distinct tolerability profile and shows varying antitumor activity across BRAFi-pretreated and BRAFi-naïve patients with advanced/metastatic stage melanoma 3.

Encorafenib inhibited in vitro growth of tumor cell lines expressing BRAF V600 E, D, and K mutations. In mice implanted with tumor cells expressing BRAF V600E, encorafenib induced tumor regressions associated with RAF/MEK/ERK pathway suppression.5

Encorafenib and binimetinib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared with either drug alone, the co-administration of encorafenib and binimetinib resulted 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. Additionally, the combination of encorafenib and binimetinib delayed the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared to either drug alone. In a BRAF V600E mutant NSCLC patient-derived xenograft model in mice, coadministration of encorafenib and binimetinib resulted in greater anti-tumor activity compared to binimetinib alone, with respect to tumor growth inhibition. Increased tumor growth delay after dosing cessation was also observed with the co-administration compared to either drug alone.5

In the setting of BRAF-mutant CRC, induction of EGFR-mediated MAPK pathway activation has been identified as a mechanism of resistance to BRAF inhibitors. Combinations of a BRAF inhibitor and agents targeting EGFR have been shown to overcome this resistance mechanism in nonclinical models. The co-administration of encorafenib and cetuximab had an anti-tumor effect greater than either drug alone, in a mouse model of colorectal cancer with mutated BRAF V600E.5

Mechanism of action

Encorafenib is a kinase inhibitor that targets BRAF V600E, as well as wild-type BRAF and CRAF in in vitro cell-free assays with IC50 values of 0.35, 0.47, and 0.3 nM, respectively. Mutations in the BRAF gene, such as BRAF V600E, can result in constitutively activated BRAF kinases that may stimulate tumor cell growth. Encorafenib was also able to bind to other kinases in vitro including JNK1, JNK2, JNK3, LIMK1, LIMK2, MEK4, and STK36, and reduce ligand binding to these kinases at clinically achievable concentrations (≤0.9 µM).5

TargetActionsOrganism
ASerine/threonine-protein kinase B-raf
inhibitor
Humans
AG1/S-specific cyclin-D1
inhibitor
Humans
ARAF proto-oncogene serine/threonine-protein kinase
inhibitor
Humans
AMitogen-activated protein kinase 8
inhibitor
Humans
AMitogen-activated protein kinase 9
inhibitor
Humans
AMitogen-activated protein kinase 10
inhibitor
Humans
ALIM domain kinase 1
inhibitor
Humans
ALIM domain kinase 2
inhibitor
Humans
ADual specificity mitogen-activated protein kinase kinase 4
inhibitor
Humans
ASerine/threonine-protein kinase 36
inhibitor
Humans
Absorption

The pharmacokinetics of encorafenib were studied in healthy subjects and patients with solid tumors, including advanced and unresectable or metastatic cutaneous melanoma harboring a BRAF V600E or V600K mutation, BRAF V600E mutation-positive metastatic CRC. After a single dose, systemic exposure of encorafenib was dose-proportional over the dose range of 50 mg to 700 mg (0.1 to 1.6 times the maximum recommended dose of 450 mg). After once-daily dosing, systemic exposure of encorafenib was less than dose-proportional over the dose range of 50 mg to 800 mg (0.1 to 1.8 times the maximum recommended dose of 450 mg). Steady-state was reached within 15 days, with exposure being 50% lower compared to Day 1; intersubject variability (CV%) of AUC ranged from 12% to 69%.5

After oral administration, the median Tmax of encorafenib is 2 hours. At least 86% of the dose is absorbed.5

Following administration of a single dose of encorafenib 100 mg (0.2 times the maximum recommended dose of 450 mg) with a high-fat, high-calorie meal (consisting of approximately 150 calories from protein, 350 calories from carbohydrates, and 500 calories from fat) the mean maximum encorafenib concentration (Cmax) decreased by 36% and there was no effect on AUC.5

Volume of distribution

The blood-to-plasma concentration ratio is 0.58. The geometric mean (CV%) of apparent volume of distribution is 164 L (70%).4

Protein binding

Encorafenib is 86% bound to human plasma proteins in vitro.4

Metabolism

Encorafenib is primarily metabolized by CYP3A4 (83%) and to a lesser extent by CYP2C19 (16%) and CYP2D6 (1%).5

Route of elimination

Following a single oral dose of 100 mg radiolabeled encorafenib, 47% (5% unchanged) of the administered dose was recovered in the feces and 47% (2% unchanged) was recovered in the urine.4

Half-life

The mean (CV%) terminal half-life (t1/2) of encorafenib is 3.5 hours (17%).4

Clearance

The apparent clearance is 14 L/h (54%) at day 1, increasing to 32 L/h (59%) at steady-state.4

Adverse Effects
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Toxicity

New primary malignancies, cutaneous and non-cutaneous, have been observed in patients treated with BRAF inhibitors and can occur with encorafenib.4

In COLUMBUS, a phase 3 safety and efficacy trial,4 cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma (KA), occurred in 2.6%, and basal cell carcinoma occurred in 1.6% of patients who received BRAFTOVI in combination with binimetinib. The median time to first occurrence of cuSCC/KA was 5.8 months (range 1 to 9 months).4

Tumor promotion in BRAF Wild-Type Tumors has been observed with encofarenib use.4

Hemorrhage, uveitis, QT interval prolongation are also other adverse events observed while taking this medication.4

Encorafenib, when used as a single agent, is associated with an increased risk of certain adverse reactions compared to when BRAFTOVI is used in combination with binimetinib. Grades 3 or 4 dermatologic reactions occurred in 21% of patients treated with BRAFTOVI therapy alone compared to 2% of patients treated with BRAFTOVI in combination with binimetinib.4

Advise females with reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with BRAFTOVI and for 2 weeks after the final dose.4

Carcinogenicity studies with encorafenib have not been conducted. Encorafenib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, or micronuclei in the bone marrow of rats.5

No dedicated fertility studies were performed with encorafenib in animals. In a general toxicology study in rats, decreased testes and epididymis weights, tubular degeneration in testes, and oligospermia in epididymides were observed at doses approximately 13 times the human exposure at the 450 mg clinical dose based on AUC. No effects on reproductive organs were observed in either sex in any of the non-human primate toxicity studies.5

Since encorafenib is 86% bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with encorafenib.5

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirThe metabolism of Abacavir can be decreased when combined with Encorafenib.
AbametapirThe serum concentration of Encorafenib can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Encorafenib can be increased when combined with Abatacept.
AbemaciclibThe serum concentration of Abemaciclib can be decreased when it is combined with Encorafenib.
AbirateroneThe metabolism of Encorafenib can be decreased when combined with Abiraterone.
Food Interactions
  • Avoid grapefruit products. Grapefruit inhibits CYP3A metabolism, which may increase the serum concentration of encorafenib.
  • Exercise caution with St. John's Wort. This herb induces CYP3A metabolism, which may reduce serum levels of encorafenib.
  • Take with or without food.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
BraftoviCapsule75 mgOralPierre Fabre Médicament2021-03-17Not applicableEU flag
BraftoviCapsule75 mgOralPfizer Canada Ulc2021-07-05Not applicableCanada flag
BraftoviCapsule75 mgOralPierre Fabre Médicament2021-03-17Not applicableEU flag
BraftoviCapsule50 mgOralPierre Fabre Médicament2021-03-17Not applicableEU flag
BraftoviCapsule75 mg/1OralArray BioPharma Inc.2018-06-27Not applicableUS flag

Categories

ATC Codes
L01EC03 — Encorafenib
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as phenylpyrazoles. These are compounds containing a phenylpyrazole skeleton, which consists of a pyrazole bound to a phenyl group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Azoles
Sub Class
Pyrazoles
Direct Parent
Phenylpyrazoles
Alternative Parents
Sulfanilides / Aminopyrimidines and derivatives / Chlorobenzenes / Fluorobenzenes / Organosulfonamides / Aryl chlorides / Aryl fluorides / Organic sulfonamides / Heteroaromatic compounds / Aminosulfonyl compounds
show 8 more
Substituents
Amine / Aminopyrimidine / Aminosulfonyl compound / Aromatic heteromonocyclic compound / Aryl chloride / Aryl fluoride / Aryl halide / Azacycle / Benzenoid / Carbamic acid ester
show 25 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
8L7891MRB6
CAS number
1269440-17-6
InChI Key
CMJCXYNUCSMDBY-ZDUSSCGKSA-N
InChI
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
IUPAC Name
methyl N-[(2S)-1-({4-[3-(5-chloro-2-fluoro-3-methanesulfonamidophenyl)-1-(propan-2-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate
SMILES
COC(=O)N[C@@H](C)CNC1=NC=CC(=N1)C1=CN(N=C1C1=CC(Cl)=CC(NS(C)(=O)=O)=C1F)C(C)C

References

General References
  1. Moschos SJ, Pinnamaneni R: Targeted therapies in melanoma. Surg Oncol Clin N Am. 2015 Apr;24(2):347-58. doi: 10.1016/j.soc.2014.12.011. Epub 2015 Jan 24. [Article]
  2. BRAF B-Raf proto-oncogene, serine/threonine kinase [ Homo sapiens (human) ] [Link]
  3. Phase I Dose-Escalation and -Expansion Study of the BRAF Inhibitor Encorafenib (LGX818) in Metastatic BRAF-Mutant Melanoma [Link]
  4. FDA Approved Drug Products: Braftovi (encorafenib) oral capsules [Link]
  5. FDA Approved Drug Products: BRAFTOVI® (encorafenib) capsules, for oral use (October 2023) [Link]
  6. Encorafenib review [File]
Human Metabolome Database
HMDB0304887
PubChem Compound
50922675
PubChem Substance
347828081
ChemSpider
28536139
BindingDB
221688
RxNav
2049106
ChEMBL
CHEMBL3301612
ZINC
ZINC000068249103
PharmGKB
PA166179872
Wikipedia
Encorafenib
MSDS
Download (22.4 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4RecruitingTreatmentSolid Tumors1
3Active Not RecruitingTreatmentMelanoma3
3CompletedTreatmentBRAF V600E-mutant Metastatic Colorectal Cancer1
3Not Yet RecruitingTreatmentBiliary Tract Neoplasms1
3RecruitingTreatmentMetastatic Colorectal Cancer (CRC) / Stage III Colorectal Cancer1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral50 MG
CapsuleOral50 mg/1
CapsuleOral75 mg
CapsuleOral75 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9763941No2017-09-192032-11-21US flag
US9314464No2016-04-192031-07-04US flag
US9850229No2017-12-262030-08-27US flag
US8541575No2013-09-242030-02-26US flag
US10005761No2018-06-262030-08-27US flag
US9850230No2017-12-262030-08-27US flag
US9593099No2017-03-142030-08-27US flag
US9593100No2017-03-142030-08-27US flag
US8946250No2015-02-032029-07-23US flag
US9387208No2016-07-122032-11-21US flag
US8501758No2013-08-062031-03-04US flag
US10258622No2019-04-162032-11-21US flag
US9474754No2016-10-252033-08-05US flag
USRE49556No2010-02-272030-02-27US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0112 mg/mLALOGPS
logP4.16ALOGPS
logP2.65Chemaxon
logS-4.7ALOGPS
pKa (Strongest Acidic)8.45Chemaxon
pKa (Strongest Basic)3.08Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count7Chemaxon
Hydrogen Donor Count3Chemaxon
Polar Surface Area140.13 Å2Chemaxon
Rotatable Bond Count9Chemaxon
Refractivity145.6 m3·mol-1Chemaxon
Polarizability54.11 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0006-0000290000-4cc30bed5acf482d632a
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-053i-3000940000-5d4239ceadea71c35f3b
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-01e9-1000910000-d4248990687025aba1d9
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-004r-2000900000-46680cb992a0eacff357
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-00e9-1003910000-c6e1628cf8d3d66126eb
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0und-7802900000-cdd56cdd700ae9ad128b
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-209.96346
predicted
DeepCCS 1.0 (2019)
[M+H]+212.35901
predicted
DeepCCS 1.0 (2019)
[M+Na]+218.27153
predicted
DeepCCS 1.0 (2019)

Targets

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Use our structured and evidence-based datasets to unlock new
insights and accelerate drug research.
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
Curator comments
Inhibit both WT and V600E BRAF
General Function
Protein serine/threonine kinase activity
Specific Function
Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus. May play a role in the postsynaptic responses of hippocampal neuron. Phosphorylates MAP2K1, a...
Gene Name
BRAF
Uniprot ID
P15056
Uniprot Name
Serine/threonine-protein kinase B-raf
Molecular Weight
84436.135 Da
References
  1. Li Z, Jiang K, Zhu X, Lin G, Song F, Zhao Y, Piao Y, Liu J, Cheng W, Bi X, Gong P, Song Z, Meng S: Encorafenib (LGX818), a potent BRAF inhibitor, induces senescence accompanied by autophagy in BRAFV600E melanoma cells. Cancer Lett. 2016 Jan 28;370(2):332-44. doi: 10.1016/j.canlet.2015.11.015. Epub 2015 Nov 14. [Article]
  2. Koelblinger P, Thuerigen O, Dummer R: Development of encorafenib for BRAF-mutated advanced melanoma. Curr Opin Oncol. 2018 Mar;30(2):125-133. doi: 10.1097/CCO.0000000000000426. [Article]
  3. Moschos SJ, Pinnamaneni R: Targeted therapies in melanoma. Surg Oncol Clin N Am. 2015 Apr;24(2):347-58. doi: 10.1016/j.soc.2014.12.011. Epub 2015 Jan 24. [Article]
  4. FDA Approved Drug Products: BRAFTOVI® (encorafenib) capsules, for oral use (October 2023) [Link]
  5. Encorafenib review [File]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Transcription factor binding
Specific Function
Regulatory component of the cyclin D1-CDK4 (DC) complex that phosphorylates and inhibits members of the retinoblastoma (RB) protein family including RB1 and regulates the cell-cycle during G(1)/S t...
Gene Name
CCND1
Uniprot ID
P24385
Uniprot Name
G1/S-specific cyclin-D1
Molecular Weight
33728.74 Da
References
  1. Li Z, Jiang K, Zhu X, Lin G, Song F, Zhao Y, Piao Y, Liu J, Cheng W, Bi X, Gong P, Song Z, Meng S: Encorafenib (LGX818), a potent BRAF inhibitor, induces senescence accompanied by autophagy in BRAFV600E melanoma cells. Cancer Lett. 2016 Jan 28;370(2):332-44. doi: 10.1016/j.canlet.2015.11.015. Epub 2015 Nov 14. [Article]
  2. Dummer R, Ascierto PA, Gogas HJ, Arance A, Mandala M, Liszkay G, Garbe C, Schadendorf D, Krajsova I, Gutzmer R, Chiarion-Sileni V, Dutriaux C, de Groot JWB, Yamazaki N, Loquai C, Moutouh-de Parseval LA, Pickard MD, Sandor V, Robert C, Flaherty KT: Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):603-615. doi: 10.1016/S1470-2045(18)30142-6. Epub 2018 Mar 21. [Article]
  3. Encorafenib review [File]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Protein serine/threonine kinase activity
Specific Function
Serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade, and this critical regulatory link functions as a switch determin...
Gene Name
RAF1
Uniprot ID
P04049
Uniprot Name
RAF proto-oncogene serine/threonine-protein kinase
Molecular Weight
73051.025 Da
References
  1. FDA Approved Drug Products: BRAFTOVI® (encorafenib) capsules, for oral use (October 2023) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Protein serine/threonine kinase activity
Specific Function
Serine/threonine-protein kinase involved in various processes such as cell proliferation, differentiation, migration, transformation and programmed cell death. Extracellular stimuli such as proinfl...
Gene Name
MAPK8
Uniprot ID
P45983
Uniprot Name
Mitogen-activated protein kinase 8
Molecular Weight
48295.14 Da
References
  1. FDA Approved Drug Products: BRAFTOVI® (encorafenib) capsules, for oral use (October 2023) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Transcription factor binding
Specific Function
Serine/threonine-protein kinase involved in various processes such as cell proliferation, differentiation, migration, transformation and programmed cell death. Extracellular stimuli such as proinfl...
Gene Name
MAPK9
Uniprot ID
P45984
Uniprot Name
Mitogen-activated protein kinase 9
Molecular Weight
48138.655 Da
References
  1. FDA Approved Drug Products: BRAFTOVI® (encorafenib) capsules, for oral use (October 2023) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Map kinase kinase activity
Specific Function
Serine/threonine-protein kinase involved in various processes such as neuronal proliferation, differentiation, migration and programmed cell death. Extracellular stimuli such as proinflammatory cyt...
Gene Name
MAPK10
Uniprot ID
P53779
Uniprot Name
Mitogen-activated protein kinase 10
Molecular Weight
52585.015 Da
References
  1. FDA Approved Drug Products: BRAFTOVI® (encorafenib) capsules, for oral use (October 2023) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Zinc ion binding
Specific Function
Serine/threonine-protein kinase that plays an essential role in the regulation of actin filament dynamics. Acts downstream of several Rho family GTPase signal transduction pathways. Activated by up...
Gene Name
LIMK1
Uniprot ID
P53667
Uniprot Name
LIM domain kinase 1
Molecular Weight
72584.4 Da
References
  1. FDA Approved Drug Products: BRAFTOVI® (encorafenib) capsules, for oral use (October 2023) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Displays serine/threonine-specific phosphorylation of myelin basic protein and histone (MBP) in vitro.
Specific Function
Atp binding
Gene Name
LIMK2
Uniprot ID
P53671
Uniprot Name
LIM domain kinase 2
Molecular Weight
72231.335 Da
References
  1. FDA Approved Drug Products: BRAFTOVI® (encorafenib) capsules, for oral use (October 2023) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Essential component of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. With MAP2K7/MKK7, is the one of the only known kinase to directly activate the stress-activated protein kinase/c-Jun N-terminal kinases MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3. MAP2K4/MKK4 and MAP2K7/MKK7 both activate the JNKs by phosphorylation, but they differ in their preference for the phosphorylation site in the Thr-Pro-Tyr motif. MAP2K4 shows preference for phosphorylation of the Tyr residue and MAP2K7/MKK7 for the Thr residue. The phosphorylation of the Thr residue by MAP2K7/MKK7 seems to be the prerequisite for JNK activation at least in response to proinflammatory cytokines, while other stimuli activate both MAP2K4/MKK4 and MAP2K7/MKK7 which synergistically phosphorylate JNKs. MAP2K4 is required for maintaining peripheral lymphoid homeostasis. The MKK/JNK signaling pathway is also involved in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis. Whereas MAP2K7/MKK7 exclusively activates JNKs, MAP2K4/MKK4 additionally activates the p38 MAPKs MAPK11, MAPK12, MAPK13 and MAPK14.
Specific Function
Atp binding
Gene Name
MAP2K4
Uniprot ID
P45985
Uniprot Name
Dual specificity mitogen-activated protein kinase kinase 4
Molecular Weight
44287.34 Da
References
  1. FDA Approved Drug Products: BRAFTOVI® (encorafenib) capsules, for oral use (October 2023) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Serine/threonine protein kinase which plays an important role in the sonic hedgehog (Shh) pathway by regulating the activity of GLI transcription factors (PubMed:10806483). Controls the activity of the transcriptional regulators GLI1, GLI2 and GLI3 by opposing the effect of SUFU and promoting their nuclear localization (PubMed:10806483). GLI2 requires an additional function of STK36 to become transcriptionally active, but the enzyme does not need to possess an active kinase catalytic site for this to occur (PubMed:10806483). Required for postnatal development, possibly by regulating the homeostasis of cerebral spinal fluid or ciliary function (By similarity). Essential for construction of the central pair apparatus of motile cilia.
Specific Function
Atp binding
Gene Name
STK36
Uniprot ID
Q9NRP7
Uniprot Name
Serine/threonine-protein kinase 36
Molecular Weight
143993.57 Da
References
  1. FDA Approved Drug Products: BRAFTOVI® (encorafenib) capsules, for oral use (October 2023) [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. FDA Approved Drug Products: BRAFTOVI® (encorafenib) capsules, for oral use (October 2023) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. FDA Approved Drug Products: BRAFTOVI® (encorafenib) capsules, for oral use (October 2023) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. FDA Approved Drug Products: BRAFTOVI® (encorafenib) capsules, for oral use (October 2023) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. FDA Approved Drug Products: BRAFTOVI® (encorafenib) capsules, for oral use (October 2023) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. Koelblinger P, Thuerigen O, Dummer R: Development of encorafenib for BRAF-mutated advanced melanoma. Curr Opin Oncol. 2018 Mar;30(2):125-133. doi: 10.1097/CCO.0000000000000426. [Article]
  2. FDA Approved Drug Products: BRAFTOVI® (encorafenib) capsules, for oral use (October 2023) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. FDA Approved Drug Products: BRAFTOVI® (encorafenib) capsules, for oral use (October 2023) [Link]
  2. Encorafenib review [File]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
Inducer
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. FDA Approved Drug Products: BRAFTOVI® (encorafenib) capsules, for oral use (October 2023) [Link]
  2. Encorafenib review [File]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. FDA Approved Drug Products: BRAFTOVI® (encorafenib) capsules, for oral use (October 2023) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A7
Uniprot ID
P24462
Uniprot Name
Cytochrome P450 3A7
Molecular Weight
57525.03 Da
References
  1. FDA Approved Drug Products: BRAFTOVI® (encorafenib) capsules, for oral use (October 2023) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A1
Uniprot ID
P22309
Uniprot Name
UDP-glucuronosyltransferase 1-1
Molecular Weight
59590.91 Da
References
  1. FDA Approved Drug Products: BRAFTOVI® (encorafenib) capsules, for oral use (October 2023) [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Cavalieri G, Cilurzo G, Pettorosso L, Mansueto A, Laurini E, Pricl S: Biophysical and docking study on the interaction of anticancer drugs encorafenib and binimetinib with human serum albumin. Eur J Pharm Sci. 2023 Oct 1;189:106550. doi: 10.1016/j.ejps.2023.106550. Epub 2023 Jul 30. [Article]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. FDA Approved Drug Products: BRAFTOVI® (encorafenib) capsules, for oral use (October 2023) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Quaternary ammonium group transmembrane transporter activity
Specific Function
Mediates tubular uptake of organic compounds from circulation. Mediates the influx of agmatine, dopamine, noradrenaline (norepinephrine), serotonin, choline, famotidine, ranitidine, histamin, creat...
Gene Name
SLC22A2
Uniprot ID
O15244
Uniprot Name
Solute carrier family 22 member 2
Molecular Weight
62579.99 Da
References
  1. FDA Approved Drug Products: BRAFTOVI® (encorafenib) capsules, for oral use (October 2023) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. FDA Approved Drug Products: BRAFTOVI® (encorafenib) capsules, for oral use (October 2023) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one ...
Gene Name
SLC22A6
Uniprot ID
Q4U2R8
Uniprot Name
Solute carrier family 22 member 6
Molecular Weight
61815.78 Da
References
  1. FDA Approved Drug Products: BRAFTOVI® (encorafenib) capsules, for oral use (October 2023) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenad...
Gene Name
SLC22A8
Uniprot ID
Q8TCC7
Uniprot Name
Solute carrier family 22 member 8
Molecular Weight
59855.585 Da
References
  1. FDA Approved Drug Products: BRAFTOVI® (encorafenib) capsules, for oral use (October 2023) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
References
  1. FDA Approved Drug Products: BRAFTOVI® (encorafenib) capsules, for oral use (October 2023) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
Gene Name
SLCO1B3
Uniprot ID
Q9NPD5
Uniprot Name
Solute carrier organic anion transporter family member 1B3
Molecular Weight
77402.175 Da
References
  1. FDA Approved Drug Products: BRAFTOVI® (encorafenib) capsules, for oral use (October 2023) [Link]

Drug created at October 20, 2016 20:42 / Updated at March 03, 2024 18:31