Encorafenib

Braftovi
Clinical data
ATC code	None;
Legal status
Legal status	Approved;
Identifiers
	IUPAC name Methyl [(2S)-1-{[4-(3-{5-chloro-2-fluoro-3-[(methylsulfonyl)amino]phenyl}-1-isopropyl-1H-pyrazol-4-yl)-2-pyrimidinyl]amino}-2-propanyl]carbamate;
CAS Number	1269440-17-6;
PubChem CID	50922675;
DrugBank	DB11718;
ChemSpider	28536139;
UNII	8L7891MRB6;
ChEMBL	ChEMBLCHEMBL3301612;
CompTox Dashboard (EPA)	DTXSID00155347 ;
Chemical and physical data
Formula	C22H27ClFN7O4S
Molar mass	540.011 g/mol g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C[C@@H](CNc1nccc(n1)c2cn(nc2c3cc(cc(c3F)NS(=O)(=O)C)Cl)C(C)C)NC(=O)OC;
	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; Key:CMJCXYNUCSMDBY-ZDUSSCGKSA-N;

Encorafenib, also known as Braftovi and LGX818 is a drug for the treatment of certain melanomas. It is a small molecule BRAF inhibitor ^[1] that targets key enzymes in the MAPK signaling pathway. This pathway occurs in many different cancers including melanoma and colorectal cancers.^[2] The substance was being developed by Novartis and then by Array BioPharma. In June 2018 it was approved by the FDA in combination with binimetinib for the treatment of patients with unresectable or metastatic BRAF V600E or V600K mutation-positive melanoma.^[3]

Pharmacology

Encorafenib acts as an ATP-competitive RAF kinase inhibitor, decreasing ERK phosphorylation and down-regulation of CyclinD1.^[4] This arrests the cell cycle in G1 phase, inducing senescence without apoptosis.^[4] Therefore it is only effective in melanomas with a BRAF mutation, which make up 50% of all melanomas.^[5] The plasma elimination half-life of encorafenib is approximately 6 hours, occurring mainly through metabolism via cytochrome P450 enzymes.^[6]

Clinical trials

Several clinical trials of LGX818, either alone or in combinations with the MEK inhibitor MEK162,^[7] are being run. As a result of a successful Phase Ib/II trials, Phase III trials are currently being initiated.^[8]

References

^ Koelblinger P, Thuerigen O, Dummer R (March 2018). "Development of encorafenib for BRAF-mutated advanced melanoma". Current Opinion in Oncology. 30 (2): 125–133. doi:10.1097/CCO.0000000000000426. PMC 5815646. PMID 29356698.
^ Burotto M, Chiou VL, Lee JM, Kohn EC (November 2014). "The MAPK pathway across different malignancies: a new perspective". Cancer. 120 (22): 3446–56. doi:10.1002/cncr.28864. PMC 4221543. PMID 24948110.
^ Research, Center for Drug Evaluation and. "Approved Drugs - FDA approves encorafenib and binimetinib in combination for unresectable or metastatic melanoma with BRAF mutations". www.fda.gov. Retrieved 2018-06-28.
^ ^a ^b 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 (January 2016). "Encorafenib (LGX818), a potent BRAF inhibitor, induces senescence accompanied by autophagy in BRAFV600E melanoma cells". Cancer Letters. 370 (2): 332–44. doi:10.1016/j.canlet.2015.11.015. PMID 26586345.
^ Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, et al. (July 2012). "A landscape of driver mutations in melanoma". Cell. 150 (2): 251–63. doi:10.1016/j.cell.2012.06.024. PMC 3600117. PMID 22817889.
^ Koelblinger P, Thuerigen O, Dummer R (March 2018). "Development of encorafenib for BRAF-mutated advanced melanoma". Current Opinion in Oncology. 30 (2): 125–133. doi:10.1097/CCO.0000000000000426. PMC 5815646. PMID 29356698.
^ "18 Studies found for: LGX818". Clinicaltrials.gove.
^ Clinical trial number NCT01909453 for "Study Comparing Combination of LGX818 Plus MEK162 and LGX818 Monotherapy Versus Vemurafenib in BRAF Mutant Melanoma (COLUMBUS)" at ClinicalTrials.gov

[1] Koelblinger P, Thuerigen O, Dummer R (March 2018). "Development of encorafenib for BRAF-mutated advanced melanoma". Current Opinion in Oncology. 30 (2): 125–133. doi:10.1097/CCO.0000000000000426. PMC 5815646. PMID 29356698.

[2] Burotto M, Chiou VL, Lee JM, Kohn EC (November 2014). "The MAPK pathway across different malignancies: a new perspective". Cancer. 120 (22): 3446–56. doi:10.1002/cncr.28864. PMC 4221543. PMID 24948110.

[3] Research, Center for Drug Evaluation and. "Approved Drugs - FDA approves encorafenib and binimetinib in combination for unresectable or metastatic melanoma with BRAF mutations". www.fda.gov. Retrieved 2018-06-28.

[Li_2016-4] 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 (January 2016). "Encorafenib (LGX818), a potent BRAF inhibitor, induces senescence accompanied by autophagy in BRAFV600E melanoma cells". Cancer Letters. 370 (2): 332–44. doi:10.1016/j.canlet.2015.11.015. PMID 26586345.

[5] Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, et al. (July 2012). "A landscape of driver mutations in melanoma". Cell. 150 (2): 251–63. doi:10.1016/j.cell.2012.06.024. PMC 3600117. PMID 22817889.

[6] Koelblinger P, Thuerigen O, Dummer R (March 2018). "Development of encorafenib for BRAF-mutated advanced melanoma". Current Opinion in Oncology. 30 (2): 125–133. doi:10.1097/CCO.0000000000000426. PMC 5815646. PMID 29356698.

[7] "18 Studies found for: LGX818". Clinicaltrials.gove.

[NCT01909453-8] Clinical trial number NCT01909453 for "Study Comparing Combination of LGX818 Plus MEK162 and LGX818 Monotherapy Versus Vemurafenib in BRAF Mutant Melanoma (COLUMBUS)" at ClinicalTrials.gov

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