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Cobimetinib

Cobimetinib

Synopsis, Chemistry

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Also known as: 934660-93-2, Gdc-0973, Xl518, Xl-518, Gdc 0973, Rg7420

Molecular Formula

C₂₁H₂₁F₃IN₃O₂

Molecular Weight

531.3 g/mol

InChI Key

BSMCAPRUBJMWDF-KRWDZBQOSA-N

FDA UNII

ER29L26N1X

Cobimetinib is an orally bioavailable small-molecule inhibitor of mitogen-activated protein kinase kinase 1 (MAP2K1 or MEK1), with potential antineoplastic activity. Cobimetinib specifically binds to and inhibits the catalytic activity of MEK1, resulting in inhibition of extracellular signal-related kinase 2 (ERK2) phosphorylation and activation and decreased tumor cell proliferation. Preclinical studies have demonstrated that this agent is effective in inhibiting the growth of tumor cells bearing a B-RAF mutation, which has been found to be associated with many tumor types. A threonine-tyrosine kinase and a key component of the RAS/RAF/MEK/ERK signaling pathway that is frequently activated in human tumors, MEK1 is required for the transmission of growth-promoting signals from numerous receptor tyrosine kinases.

Cobimetinib is a Kinase Inhibitor. The mechanism of action of cobimetinib is as a Kinase Inhibitor.

1 2D Structure

Cobimetinib

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

[3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]-[3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl]methanone

2.1.2 InChI

InChI=1S/C21H21F3IN3O2/c22-14-6-5-13(19(18(14)24)27-16-7-4-12(25)9-15(16)23)20(29)28-10-21(30,11-28)17-3-1-2-8-26-17/h4-7,9,17,26-27,30H,1-3,8,10-11H2/t17-/m0/s1

2.1.3 InChI Key

BSMCAPRUBJMWDF-KRWDZBQOSA-N

2.1.4 Canonical SMILES

C1CCNC(C1)C2(CN(C2)C(=O)C3=C(C(=C(C=C3)F)F)NC4=C(C=C(C=C4)I)F)O

2.1.5 Isomeric SMILES

C1CCN[C@@H](C1)C2(CN(C2)C(=O)C3=C(C(=C(C=C3)F)F)NC4=C(C=C(C=C4)I)F)O

2.2 Other Identifiers

2.2.1 UNII

ER29L26N1X

2.3 Synonyms

2.3.1 MeSH Synonyms

1. (3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)(3-hydroxy-3-(piperidin-2-yl)azetidin-1-yl)methanone

2. Cotellic

3. Gdc-0973

4. Xl518

2.3.2 Depositor-Supplied Synonyms

1. 934660-93-2

2. Gdc-0973

3. Xl518

4. Xl-518

5. Gdc 0973

6. Rg7420

7. Xl 518

8. Rg 7420

9. Er29l26n1x

10. Chembl2146883

11. [3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]-[3-hydroxy-3-[(2s)-piperidin-2-yl]azetidin-1-yl]methanone

12. Cobimetinib (gdc-0973, Rg7420)

13. (s)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)(3-hydroxy-3-(piperidin-2-yl)azetidin-1-yl)methanone

14. [3,4-bis(fluoranyl)-2-[(2-fluoranyl-4-iodanyl-phenyl)amino]phenyl]-[3-oxidanyl-3-[(2s)-piperidin-2-yl]azetidin-1-yl]methanone

15. Methanone, (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)phenyl)(3-hydroxy-3-((2s)-2-piperidinyl)-1-azetidinyl)-

16. [3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-phenyl]-((s)-3-hydroxy-3-piperidin-2-yl-azetidin-1-yl)-methanone

17. Eui

18. Cobimetinib Butyrate

19. Cobimetinib [usan]

20. 934660-94-3

21. Cobimetinib [usan:inn]

22. Cometinib

23. Unii-er29l26n1x

24. C21h21f3in3o2

25. Cobimetinib [mi]

26. Cobimetinib [inn]

27. Cobimetinib (usan/inn)

28. Cobimetinib [who-dd]

29. Schembl189565

30. Gtpl7626

31. Xl518;rg7420;cobimetinib

32. Chebi:90851

33. Dtxsid60239435

34. Ex-a673

35. Gdc0973

36. Gdc0973; Xl518; Cobimetinib

37. Bdbm50391802

38. Mfcd22124461

39. Nsc768068

40. Nsc781257

41. Nsc800075

42. S8041

43. Zinc60325170

44. Bcp9000716

45. Ccg-264727

46. Cs-0521

47. Db05239

48. Nsc-768068

49. Nsc-781257

50. Nsc-800075

51. Vs-0129

52. Xl518 (gdc-0973)

53. Ncgc00346455-03

54. Ncgc00346455-05

55. (3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)(3-hydroxy-3-(piperidin-2-yl)azetidin-1-yl)methanone

56. (s)-(3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)phenyl)(3-hydroxy-3-(piperidin-2-yl)azetidin-1-yl)methanone

57. Hy-13064

58. Ro-5514041

59. D10405

60. J-525162

61. Q15708292

62. ((3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl)(3-hydroxy-3-((2s)-piperidin-2-yl)azetidin-1-yl)methanone

63. (3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)(3-hydroxy-3-((s)-piperidin-2-yl)cyclobutyl)methanone

64. [3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]-[3-hydroxy-3-[(2s)-piperidin-2-yl]azetidin

65. [3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]{3-hydroxy-3-[(2s)-piperidin-2-yl]azetidin-1-yl}methanone

66. [3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl]-[3-hydroxy-3-[(2s)-piperidin-2-yl]azetidin-1-yl]methanone

67. {3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}{3-hydroxy-3-[(2s)-piperidin-2-yl]azetidin-1-yl}methanone

2.4 Create Date

2007-07-23

3 Chemical and Physical Properties

Molecular Formula	C₂₁H₂₁F₃IN₃O₂
Molecular Weight	531.3 g/mol
XLogP3	3.9
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	7
Rotatable Bond Count	4
Exact Mass	531.06306 g/mol
Monoisotopic Mass	531.06306 g/mol
Topological Polar Surface Area	64.6 Å²
Heavy Atom Count	30
Formal Charge	0
Complexity	624
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

For the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation. Cobimetinib is used in combination with vemurafenib, a BRAF inhibitor.

FDA Label

Cotellic is indicated for use in combination with vemurafenib for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation.

Treatment of all conditions included in the category of malignant neoplasms (except haematopoietic and lymphoid tissue) with Ras, Raf or MEK pathway activation

5 Pharmacology and Biochemistry

5.1 Pharmacology

Cobimetinib is a reversible inhibitor of mitogen-activated protein kinase 1 (MAPK)/extracellular signal regulated kinase 1 (MEK1) and MEK2. Preclinical studies have demonstrated that this agent is effective in inhibiting the growth of tumor cells bearing a BRAF mutation, which has been found to be associated with many tumor types. A threonine-tyrosine kinase and a key component of the RAS/RAF/MEK/ERK signalling pathway that is frequently activated in human tumors, MEK1 is required for the transmission of growth-promoting signals from numerous receptor tyrosine kinases. Cobimetinib is used in combination with vemurafenib because the clinical benefit of a BRAF inhibitor is limited by intrinsic and acquired resistance. Reactivation of the MAPK pathway is a major contributor to treatment failure in BRAF-mutant melanomas, approximately ~80% of melanoma tumors becomes BRAF-inhibitor resistant due to reactivation of MAPK signalling. BRAF-inhibitor resistant tumor cells are sensitive to MEK inhibition, therefore cobimetinib and vemurafenib will result in dual inhibition of BRAF and its downstream target, MEK.

5.2 FDA Pharmacological Classification

5.2.1 Active Moiety

COBIMETINIB

5.2.2 FDA UNII

ER29L26N1X

5.2.3 Pharmacological Classes

Kinase Inhibitors [MoA]; Kinase Inhibitor [EPC]

5.3 ATC Code

L01XE38

S76 | LUXPHARMA | Pharmaceuticals Marketed in Luxembourg | Pharmaceuticals marketed in Luxembourg, as published by d'Gesondheetskeess (CNS, la caisse nationale de sante, www.cns.lu), mapped by name to structures using CompTox by R. Singh et al. (in prep.). List downloaded from https://cns.public.lu/en/legislations/textes-coordonnes/liste-med-comm.html. Dataset DOI:10.5281/zenodo.4587355

L - Antineoplastic and immunomodulating agents

L01 - Antineoplastic agents

L01E - Protein kinase inhibitors

L01EE - Mitogen-activated protein kinase (mek) inhibitors

L01EE02 - Cobimetinib

5.4 Absorption, Distribution and Excretion

Absorption

The bioavailability of cobimetinib is 46%, the AUC and Cmax is unaffected by food.

Route of Elimination

76% of the dose was recovered in feces with 6.6% as unchanged drug. 17.8% of the dose was recovered in urine with 1.6% as unchanged drug.

Volume of Distribution

806L in cancer patients based on a population PK analysis.

Clearance

13.9L/h

5.5 Metabolism/Metabolites

Cobimetinib is mainly metabolized via CYP3A oxidation and UGT2B7 glucuronidation with no major metabolites formed.

5.6 Biological Half-Life

Average half life was 44 hours.

5.7 Mechanism of Action

MEK inhibitor Cobimetinib specifically binds to and inhibits the catalytic activity of MEK1, resulting in inhibition of extracellular signal-related kinase 2 (ERK2) phosphorylation and activation and decreased tumor cell proliferation. Cobimetinib and vemurafenib target two different kinases in the RAS/RAF/MEK/ERK pathway.