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Encorafenib

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Chemistry

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Also known as: Lgx818, 1269440-17-6, Lgx-818, Braftovi, Encorafenib (lgx818), Nvp-lgx818-nxa

Molecular Formula

C₂₂H₂₇ClFN₇O₄S

Molecular Weight

540.0 g/mol

InChI Key

CMJCXYNUCSMDBY-ZDUSSCGKSA-N

FDA UNII

8L7891MRB6

Encorafenib is an orally available Raf kinase inhibitor with potential antineoplastic activity. Encorafenib 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. 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.

1 2D Structure

Encorafenib

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

methyl N-[(2S)-1-[[4-[3-[5-chloro-2-fluoro-3-(methanesulfonamido)phenyl]-1-propan-2-ylpyrazol-4-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate

2.1.2 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

2.1.3 InChI Key

CMJCXYNUCSMDBY-ZDUSSCGKSA-N

2.1.4 Canonical SMILES

CC(C)N1C=C(C(=N1)C2=C(C(=CC(=C2)Cl)NS(=O)(=O)C)F)C3=NC(=NC=C3)NCC(C)NC(=O)OC

2.1.5 Isomeric SMILES

C[C@@H](CNC1=NC=CC(=N1)C2=CN(N=C2C3=C(C(=CC(=C3)Cl)NS(=O)(=O)C)F)C(C)C)NC(=O)OC

2.2 Other Identifiers

2.2.1 UNII

8L7891MRB6

2.3 Synonyms

2.3.1 MeSH Synonyms

1. Braftovi

2. Lgx818

2.3.2 Depositor-Supplied Synonyms

1. Lgx818

2. 1269440-17-6

3. Lgx-818

4. Braftovi

5. Encorafenib (lgx818)

6. Nvp-lgx818-nxa

7. Nvp-lgx-818-nxa

8. Nvp-lgx818

9. 8l7891mrb6

10. Methyl N-[(2s)-1-[[4-[3-[5-chloro-2-fluoro-3-(methanesulfonamido)phenyl]-1-propan-2-ylpyrazol-4-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate

11. 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

12. Encorafenib [usan:inn]

13. Unii-8l7891mrb6

14. Lgx 818

15. Braftovi (tn)

16. 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

17. Encorafenib [mi]

18. Encorafenib(lgx-818)

19. Lgx-818(encorafenib)

20. Encorafenib [inn]

21. Encorafenib [jan]

22. Encorafenib [usan]

23. Encorafenib [who-dd]

24. Encorafenib (jan/usan/inn)

25. Gtpl7908

26. Schembl8228295

27. Chembl3301612

28. Dtxsid00155347

29. Encorafenib [orange Book]

30. Bdbm221688

31. Bcp08458

32. Ex-a1587

33. Mfcd25976758

34. Nsc778304

35. Nsc800093

36. S7108

37. Zinc68249103

38. Ccg-269960

39. Db11718

40. Nsc-778304

41. Nsc-800093

42. Ncgc00378599-03

43. Ac-30230

44. As-35201

45. Hy-15605

46. A13226

47. D11053

48. Us9314464, 9

49. Q15409405

50. (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

51. 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

52. 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

2.4 Create Date

2011-03-21

3 Chemical and Physical Properties

Molecular Formula	C₂₂H₂₇ClFN₇O₄S
Molecular Weight	540.0 g/mol
XLogP3	2.7
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	10
Rotatable Bond Count	10
Exact Mass	539.1517794 g/mol
Monoisotopic Mass	539.1517794 g/mol
Topological Polar Surface Area	149 Å²
Heavy Atom Count	36
Formal Charge	0
Complexity	836
Isotope Atom Count	0
Defined Atom Stereocenter Count	1
Undefined Atom Stereocenter Count	0
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

4 Drug and Medication Information

4.1 Drug Indication

Used in combination with [Binimetinib] in metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test.

Encorafenib is indicated:

- in combination with binimetinib is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation

- in combination with cetuximab, for the treatment of adult patients with metastatic colorectal cancer (CRC) with a BRAF V600E mutation, who have received prior systemic therapy

Treatment of colorectal carcinoma

Treatment of melanoma

5 Pharmacology and Biochemistry

5.1 Pharmacology

Encorafenib has shown improved efficacy in the treatment of metastatic melanoma. Encorafenib, a selective BRAF inhibitor (BRAFi), has a pharmacologic profile that is distinct from that of other clinically active BRAFis. Once-daily dosing of single-agent encorafenib has a distinct tolerability profile and shows varying antitumor activity across BRAFi-pretreated and BRAFi-nave patients with advanced/metastatic stage melanoma.

5.2 ATC Code

L01EC03

L - Antineoplastic and immunomodulating agents

L01 - Antineoplastic agents

L01E - Protein kinase inhibitors

L01EC - B-raf serine-threonine kinase (braf) inhibitors

L01EC03 - Encorafenib

5.3 Absorption, Distribution and Excretion

Absorption

After oral administration, the median Tmax of encorafenib is 2 hours. At least 86% of the dose is absorbed. Administration of a single dose of BRAFTOVI 100 mg (0.2 times the recommended dose) with a high-fat, high-calorie meal (comprised of approximately 150 calories from protein, 350 calories from carbohydrates, and 500 calories from fat) decreased the mean maximum encorafenib concentration (Cmax) by 36% with no effect on AUC (area under the curve).

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.

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%).

Clearance

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

5.4 Metabolism/Metabolites

The primary metabolic pathway is N-dealkylation, with CYP3A4 as the main contributor (83%) to total oxidative clearance of encorafenib in human liver microsomes, followed by CYP2C19 (16%) and CYP2D6 (1%).

5.5 Biological Half-Life

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

5.6 Mechanism of Action

Encorafenib is a kinase inhibitor that specifically targets BRAF V600E, as well as wild-type BRAF and CRAF while tested with in vitro cell-free assays with IC50 values of 0.35, 0.47, and 0.3 nM, respectively. Mutations in the BRAF gene, including BRAF V600E, result in activated BRAF kinases that mahy stimulate tumor cell growth. Encorafenib is able to bind to other kinases in vitro including JNK1, JNK2, JNK3, LIMK1, LIMK2, MEK4, and STK36 and significantly reduce ligand binding to these kinases at clinically achievable concentrations ( 0.9 M). In efficacy studies, encorafenib inhibited the in vitro cell growth of tumor cell lines that express BRAF V600 E, D, and K mutations. In mice implanted with tumor cells expressing the BRAF V600E mutation, encorafenib induced tumor regressions associated with RAF/MEK/ERK pathway suppression. 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.

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