Encorafenib
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MedKoo CAT#: 205852

CAS#: 1269440-17-6

Description: Encorafenib, also known as LGX-818, is an orally available Raf kinase inhibitor with potential antineoplastic activity. LGX818 specifically inhibits Raf kinase, a serine/threonine enzyme in the RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-related kinase (ERK) signaling pathway. By inhibiting the activation of the RAF/MEK/ERK signaling pathway, the administration of LGX818 may result in a decrease in proliferation of tumor cells.


Chemical Structure

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Encorafenib
CAS# 1269440-17-6

Theoretical Analysis

MedKoo Cat#: 205852
Name: Encorafenib
CAS#: 1269440-17-6
Chemical Formula: C22H27ClFN7O4S
Exact Mass: 539.15178
Molecular Weight: 540.01
Elemental Analysis: C, 48.93; H, 5.04; Cl, 6.57; F, 3.52; N, 18.16; O, 11.85; S, 5.94

Price and Availability

Size Price Availability Quantity
10.0mg USD 125.0 Ready to ship
25.0mg USD 250.0 Ready to ship
50.0mg USD 450.0 Ready to ship
100.0mg USD 750.0 Ready to ship
200.0mg USD 1250.0 Ready to ship
500.0mg USD 2450.0 Ready to ship
1.0g USD 3950.0 Ready to ship
2.0g USD 6950.0 Ready to ship
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Related CAS #: 1269440-17-6   1269440-29-0 (R-isomer of LGX-818)    

Synonym: LGX818; LGX-818; LGX 818; Encorafenib.

IUPAC/Chemical Name: (S)-methyl (1-((4-(3-(5-chloro-2-fluoro-3-(methylsulfonamido)phenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)propan-2-yl)carbamate.

InChi Key: CMJCXYNUCSMDBY-ZDUSSCGKSA-N

InChi Code: 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

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

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Encorafenib (LGX818) is a BRAF inhibitor with selective anti-proliferative and apoptotic activity in cells expressing BRAFV600E (EC50=4 nM).
In vitro activity: The suppression of growth of colorectal cancer (CRC) cells by encorafenib was investigated. The effects of treatment of encorafenib on pathways linked to cancer were studied, and the effective inhibition of cell proliferation was documented. Cell migration was inhibited by encorafenib through a likely involvement of MPP and TIMP modulation. Furthermore, encorafenib treatment also induced cell cycle arrest. In addition, induction of apoptosis in CRC cells by elevating levels of PUMA. These observations indicate the potential therapeutic efficacy of encorafenib on CRC. Reference: Mol Cell Biochem. 2019 Sep;459(1-2):113-120. https://link.springer.com/article/10.1007%2Fs11010-019-03554-3
In vivo activity: To investigate αvβ3-integrin-targeted optoacoustic imaging and MRI for monitoring a BRAF/MEK inhibitor combination therapy in a murine model of human melanoma, human BRAF V600E-positive melanoma xenograft (A375)-bearing Balb/c nude mice (n = 10) were imaged before (day 0) and after (day 7) a BRAF/MEK inhibitor combination therapy (encorafenib, 1.3 mg/kg/d; binimetinib, 0.6 mg/kg/d, n = 5) or placebo (n = 5), respectively. Optoacoustic imaging was performed on a preclinical system unenhanced and 5 h after i. v. injection of an αvβ3-integrin-targeted fluorescent probe. The αvβ3-integrin-specific tumor signal was significantly reduced under therapy, showing a unidirectional decline in all animals (from 7.98±2.22 to 1.67±1.30; p = 0.043). No significant signal change was observed in the control group (from 6.60±6.51 to 3.67±1.93; p = 0.500). Immunohistochemistry revealed a significantly lower integrin expression (ß3: 0.20±0.02 vs. 0.39±0.05; p = 0.008) and microvascular density (CD31: 119±15 vs. 292±49; p = 0.008) in the therapy group. Reference: PLoS One. 2018 Oct 3;13(10):e0204930. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169922/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 100.0 185.18
Ethanol 100.0 185.18

Preparing Stock Solutions

The following data is based on the product molecular weight 540.01 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Li J, Li X. Encorafenib inhibits migration, induces cell cycle arrest and apoptosis in colorectal cancer cells. Mol Cell Biochem. 2019 Sep;459(1-2):113-120. doi: 10.1007/s11010-019-03554-3. Epub 2019 May 21. PMID: 31114933. 2. Kazmierczak PM, Burton NC, Keinrath G, Hirner-Eppeneder H, Schneider MJ, Eschbach RS, Heimer M, Solyanik O, Todica A, Reiser MF, Ricke J, Cyran CC. Integrin-targeted quantitative optoacoustic imaging with MRI correlation for monitoring a BRAF/MEK inhibitor combination therapy in a murine model of human melanoma. PLoS One. 2018 Oct 3;13(10):e0204930. doi: 10.1371/journal.pone.0204930. PMID: 30281669; PMCID: PMC6169922.
In vitro protocol: 1. Li J, Li X. Encorafenib inhibits migration, induces cell cycle arrest and apoptosis in colorectal cancer cells. Mol Cell Biochem. 2019 Sep;459(1-2):113-120. doi: 10.1007/s11010-019-03554-3. Epub 2019 May 21. PMID: 31114933.
In vivo protocol: 1. Kazmierczak PM, Burton NC, Keinrath G, Hirner-Eppeneder H, Schneider MJ, Eschbach RS, Heimer M, Solyanik O, Todica A, Reiser MF, Ricke J, Cyran CC. Integrin-targeted quantitative optoacoustic imaging with MRI correlation for monitoring a BRAF/MEK inhibitor combination therapy in a murine model of human melanoma. PLoS One. 2018 Oct 3;13(10):e0204930. doi: 10.1371/journal.pone.0204930. PMID: 30281669; PMCID: PMC6169922.

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1: Carr MJ, Sun J, Eroglu Z, Zager JS. An evaluation of encorafenib for the treatment of melanoma. Expert Opin Pharmacother. 2019 Nov 30:1-7. doi: 10.1080/14656566.2019.1694664. [Epub ahead of print] PubMed PMID: 31790307.

2: McLoughlin EM, Fadul CE, Patel SH, Hall RD, Gentzler RD. Clinical and Radiographic Response of Leptomeningeal and Brain Metastases to Encorafenib and Binimetinib in a Patient With BRAF V600E-Mutated Lung Adenocarcinoma. J Thorac Oncol. 2019 Dec;14(12):e269-e271. doi: 10.1016/j.jtho.2019.07.019. PubMed PMID: 31757377.

3: Gravbrot N, Sundararajan S. Severe Drug-Induced Liver Injury from Combination Encorafenib/Binimetinib. Case Rep Oncol Med. 2019 Oct 7;2019:3051945. doi: 10.1155/2019/3051945. eCollection 2019. PubMed PMID: 31687241; PubMed Central PMCID: PMC6800898.

4: Holbrook K, Lutzky J, Davies MA, Davis JM, Glitza IC, Amaria RN, Diab A, Patel SP, Amin A, Tawbi H. Intracranial antitumor activity with encorafenib plus binimetinib in patients with melanoma brain metastases: A case series. Cancer. 2019 Oct 28. doi: 10.1002/cncr.32547. [Epub ahead of print] PubMed PMID: 31658370.

5: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Available from http://www.ncbi.nlm.nih.gov/books/NBK547988/ PubMed PMID: 31643320.

6: Binimetinib plus encorafenib for metastatic melanoma. Aust Prescr. 2019 Oct;42(5):168. doi: 10.18773/austprescr.2019.057. Epub 2019 Sep 13. Review. PubMed PMID: 31631932; PubMed Central PMCID: PMC6787304.

7: Kopetz S, Grothey A, Yaeger R, Van Cutsem E, Desai J, Yoshino T, Wasan H, Ciardiello F, Loupakis F, Hong YS, Steeghs N, Guren TK, Arkenau HT, Garcia-Alfonso P, Pfeiffer P, Orlov S, Lonardi S, Elez E, Kim TW, Schellens JHM, Guo C, Krishnan A, Dekervel J, Morris V, Calvo Ferrandiz A, Tarpgaard LS, Braun M, Gollerkeri A, Keir C, Maharry K, Pickard M, Christy-Bittel J, Anderson L, Sandor V, Tabernero J. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer. N Engl J Med. 2019 Oct 24;381(17):1632-1643. doi: 10.1056/NEJMoa1908075. Epub 2019 Sep 30. PubMed PMID: 31566309.

8: Ngo P, Bycroft R. Encorafenib and binimetinib for the treatment of BRAF-mutated metastatic melanoma in the setting of combined hepatic and renal impairment. BMJ Case Rep. 2019 Sep 16;12(9). pii: e230974. doi: 10.1136/bcr-2019-230974. PubMed PMID: 31527213.

9: Gogas HJ, Flaherty KT, Dummer R, Ascierto PA, Arance A, Mandala M, Liszkay G, Garbe C, Schadendorf D, Krajsova I, Gutzmer R, Sileni VC, Dutriaux C, de Groot JWB, Yamazaki N, Loquai C, Gollerkeri A, Pickard MD, Robert C. Adverse events associated with encorafenib plus binimetinib in the COLUMBUS study: incidence, course and management. Eur J Cancer. 2019 Sep;119:97-106. doi: 10.1016/j.ejca.2019.07.016. Epub 2019 Aug 19. PubMed PMID: 31437754.

10: Li J, Li X. Encorafenib inhibits migration, induces cell cycle arrest and apoptosis in colorectal cancer cells. Mol Cell Biochem. 2019 Sep;459(1-2):113-120. doi: 10.1007/s11010-019-03554-3. Epub 2019 May 21. PubMed PMID: 31114933.

11: Rose AAN. Encorafenib and binimetinib for the treatment of BRAF V600E/K-mutated melanoma. Drugs Today (Barc). 2019 Apr;55(4):247-264. doi: 10.1358/dot.2019.55.4.2958476. Review. PubMed PMID: 31050693.

12: Livingstone E. Evaluation of cutaneous adverse events of encorafenib and binimetinb: COMMENT on article by Graf et al. J Eur Acad Dermatol Venereol. 2019 Apr;33(4):630-631. doi: 10.1111/jdv.15527. PubMed PMID: 30924242.

13: Van Cutsem E, Huijberts S, Grothey A, Yaeger R, Cuyle PJ, Elez E, Fakih M, Montagut C, Peeters M, Yoshino T, Wasan H, Desai J, Ciardiello F, Gollerkeri A, Christy-Bittel J, Maharry K, Sandor V, Schellens JHM, Kopetz S, Tabernero J. Binimetinib, Encorafenib, and Cetuximab Triplet Therapy for Patients With BRAF V600E-Mutant Metastatic Colorectal Cancer: Safety Lead-In Results From the Phase III BEACON Colorectal Cancer Study. J Clin Oncol. 2019 Jun 10;37(17):1460-1469. doi: 10.1200/JCO.18.02459. Epub 2019 Mar 20. PubMed PMID: 30892987.

14: Brue A, Benzaquen M, Bonnet N, Koeppel MC, Default A, Delaporte E, Berbis P. Desensitization protocol for angio-oedema induced by encorafenib in a patient with metastatic melanoma. J Eur Acad Dermatol Venereol. 2019 Jul;33(7):e271-e272. doi: 10.1111/jdv.15544. Epub 2019 Mar 27. PubMed PMID: 30835914.

15: Trojaniello C, Festino L, Vanella V, Ascierto PA. Encorafenib in combination with binimetinib for unresectable or metastatic melanoma with BRAF mutations. Expert Rev Clin Pharmacol. 2019 Mar;12(3):259-266. doi: 10.1080/17512433.2019.1570847. Epub 2019 Jan 24. Review. PubMed PMID: 30652516.

16: Sun J, Zager JS, Eroglu Z. Encorafenib/binimetinib for the treatment of BRAF-mutant advanced, unresectable, or metastatic melanoma: design, development, and potential place in therapy. Onco Targets Ther. 2018 Dec 14;11:9081-9089. doi: 10.2147/OTT.S171693. eCollection 2018. Review. PubMed PMID: 30588020; PubMed Central PMCID: PMC6299465.

17: Graf NP, Koelblinger P, Galliker N, Conrad S, Barysch M, Mangana J, Dummer R, Cheng PF, Goldinger SM. The spectrum of cutaneous adverse events during encorafenib and binimetinib treatment in B-rapidly accelerated fibrosarcoma-mutated advanced melanoma. J Eur Acad Dermatol Venereol. 2019 Apr;33(4):686-692. doi: 10.1111/jdv.15363. Epub 2018 Dec 13. PubMed PMID: 30468696.

18: 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. Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018 Oct;19(10):1315-1327. doi: 10.1016/S1470-2045(18)30497-2. Epub 2018 Sep 12. Erratum in: Lancet Oncol. 2018 Oct;19(10):e509. PubMed PMID: 30219628.

19: Martin-Liberal J. Encorafenib plus binimetinib: an embarrassment of riches. Lancet Oncol. 2018 Oct;19(10):1263-1264. doi: 10.1016/S1470-2045(18)30530-8. Epub 2018 Sep 12. PubMed PMID: 30219625.

20: Diamantopoulos PT, Stoungioti S, Anastasopoulou A, Papaxoinis G, Gogas H. Incomplete Vogt-Koyanagi-Harada disease following treatment with encorafenib and binimetinib for metastatic melanoma. Melanoma Res. 2018 Dec;28(6):648-651. doi: 10.1097/CMR.0000000000000505. PubMed PMID: 30169430.



Additional Information

  
 The Raf mutation BRAF V600E is frequently upregulated in a variety of human tumors and results in the constitutive activation of the RAF/MEK/ERK signaling pathway that regulates cellular proliferation and survival.