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    Cobimetinib

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    2D Structure
    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

    2D Structure

    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 Weight 531.3 g/mol
    Molecular Formula C21H21F3IN3O2
    XLogP33.9
    Hydrogen Bond Donor Count3
    Hydrogen Bond Acceptor Count7
    Rotatable Bond Count4
    Exact Mass531.06306 g/mol
    Monoisotopic Mass531.06306 g/mol
    Topological Polar Surface Area64.6 Ų
    Heavy Atom Count30
    Formal Charge0
    Complexity624
    Isotope Atom Count0
    Defined Atom Stereocenter Count1
    Undefined Atom Stereocenter Count0
    Defined Bond Stereocenter Count0
    Undefined Bond Stereocenter Count0
    Covalently Bonded Unit Count1
    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

    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.