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GSK212

Chemistry

Chemistry

Also known as: 871700-17-3, Gsk1120212, Mekinist, Gsk-1120212, Jtp 74057, Jtp-74057

Molecular Formula

C₂₆H₂₃FIN₅O₄

Molecular Weight

615.4 g/mol

InChI Key

LIRYPHYGHXZJBZ-UHFFFAOYSA-N

FDA UNII

33E86K87QN

Trametinib is an orally bioavailable inhibitor of mitogen-activated protein kinase kinase (MAP2K; MAPK/ERK kinase; MEK) 1 and 2, with potential antineoplastic activity. Upon oral administration, trametinib specifically binds to and inhibits MEK 1 and 2, resulting in an inhibition of growth factor-mediated cell signaling and cellular proliferation in various cancers. MEK 1 and 2, dual specificity serine/threonine and tyrosine kinases often upregulated in various cancer cell types, play a key role in the activation of the RAS/RAF/MEK/ERK signaling pathway that regulates cell growth.

Trametinib is a Kinase Inhibitor. The mechanism of action of trametinib is as a Protein Kinase Inhibitor.

1 2D Structure

GSK212

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

N-[3-[3-cyclopropyl-5-(2-fluoro-4-iodoanilino)-6,8-dimethyl-2,4,7-trioxopyrido[4,3-d]pyrimidin-1-yl]phenyl]acetamide

2.1.2 InChI

InChI=1S/C26H23FIN5O4/c1-13-22-21(23(31(3)24(13)35)30-20-10-7-15(28)11-19(20)27)25(36)33(17-8-9-17)26(37)32(22)18-6-4-5-16(12-18)29-14(2)34/h4-7,10-12,17,30H,8-9H2,1-3H3,(H,29,34)

2.1.3 InChI Key

LIRYPHYGHXZJBZ-UHFFFAOYSA-N

2.1.4 Canonical SMILES

CC1=C2C(=C(N(C1=O)C)NC3=C(C=C(C=C3)I)F)C(=O)N(C(=O)N2C4=CC=CC(=C4)NC(=O)C)C5CC5

2.2 Other Identifiers

2.2.1 UNII

33E86K87QN

2.3 Synonyms

2.3.1 MeSH Synonyms

1. Gsk 1120212

2. Gsk-1120212

3. Gsk1120212

4. Jtp 74057

5. Jtp-74057

6. Jtp74057

2.3.2 Depositor-Supplied Synonyms

1. 871700-17-3

2. Gsk1120212

3. Mekinist

4. Gsk-1120212

5. Jtp 74057

6. Jtp-74057

7. Gsk 1120212

8. Trametinib (gsk1120212)

9. N-[3-[3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-3,4,6,7-tetrahydro-6,8-dimethyl-2,4,7-trioxopyrido[4,3-d]pyrimidin-1(2h)-yl]phenyl]acetamide

10. Gsk212

11. Tmt212

12. Trametinib [usan]

13. Chebi:75998

14. Tmt-212

15. 33e86k87qn

16. Trametinib (usan)

17. N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2h)-yl}phenyl)acetamide

18. N-[3-[3-cyclopropyl-5-(2-fluoro-4-iodoanilino)-6,8-dimethyl-2,4,7-trioxopyrido[4,3-d]pyrimidin-1-yl]phenyl]acetamide

19. Acetamide, N-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-3,4,6,7-tetrahydro-6,8- Dimethyl-2,4,7-trioxopyrido(4,3-d)pyrimidin-1(2h)-yl)phenyl)-

20. N-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2h)-yl)phenyl)acetamide

21. Unii-33e86k87qn

22. Trametinib [usan:inn]

23. Trametinibum

24. Jtp74057

25. N-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- Tetrahydropyrido(4,3-d)pyrimidin-1(2h)-yl)phenyl)acetamide

26. N-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido(4,3-d)pyrimidin-1(2h)-yl)phenyl)acetamide

27. N-(3-{3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- Tetrahydropyrido(4,3-d)pyrimidin-1(2h)-yl}phenyl)acetamide

28. Qom

29. Trametinib [mi]

30. Trametinib (gsk1120212jtp 74057)

31. Trametinib [inn]

32. Trametinib [vandf]

33. Trametinib [who-dd]

34. Schembl170938

35. Gtpl6495

36. Gsk1120212 (trametinib)

37. Chembl2103875

38. Ex-a022

39. Bcpp000218

40. Dtxsid901007381

41. Hms3295i05

42. Hms3656j11

43. Bcp02307

44. Bdbm50531540

45. Mfcd17215075

46. Nsc758246

47. Nsc800956

48. S2673

49. Zinc43100709

50. Akos015850628

51. Am90271

52. Ccg-264976

53. Cs-0060

54. Db08911

55. Ex-5957

56. Nsc-758246

57. Nsc-800956

58. Sb16553

59. Ncgc00263180-01

60. Ncgc00263180-07

61. Ncgc00263180-14

62. Ac-25891

63. As-19382

64. Hy-10999

65. N-[3-[3-cyclopropyl-5-(2-fluoro-4-iodo-anilino)-6,8-dimethyl-2,4,7-trioxo-pyrido[4,3-d]pyrimidin-1-yl]phenyl]acetamide

66. Ft-0688438

67. Sw218089-2

68. A25168

69. D10175

70. Gsk1120212 - Jtp-74057

71. Gsk1120212,jtp-74057, Gsk212

72. Sr-01000941589

73. A1-01871

74. J-523325

75. Q7833138

76. Sr-01000941589-1

77. Brd-k12343256-001-01-4

78. Acetamide, N-[3-[3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-3,4,6,7-tetrahydro-6,8-dimethyl-2,4,7-trioxopyrido[4,3-d]pyrimidin-1(2h)-yl]phenyl]-

79. N-(3-(3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2h)-yl)phenyl)acetamide

80. N-[3-[3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-3,4,6,7-tetrahydro-6,8-dimethyl-2,4,7-trioxopyrido[4,3-d]pyrimidin-1(2h)-yl]phe Nyl]acetamide

81. N-[3-[3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxopyrido[3,4-e]pyrimidin-1-yl]phenyl]acetamide

82. N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodoanilino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2h)-yl]phenyl}ethanimidic Acid

83. N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2h-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide

2.4 Create Date

2006-10-26

3 Chemical and Physical Properties

Molecular Formula	C₂₆H₂₃FIN₅O₄
Molecular Weight	615.4 g/mol
XLogP3	3.4
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	6
Rotatable Bond Count	5
Exact Mass	615.07788 g/mol
Monoisotopic Mass	615.07788 g/mol
Topological Polar Surface Area	102 Å²
Heavy Atom Count	37
Formal Charge	0
Complexity	1090
Isotope Atom Count	0
Defined Atom Stereocenter Count	0
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

Trametinib is indicated for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test [FDA]. In May 2018, it was approved for use with [DB08912] for the treatment of treat anaplastic thyroid cancer caused by an abnormal BRAF V600E gene.

FDA Label

* Melanoma:

Trametinib as monotherapy or in combination with dabrafenib is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation (see sections 4. 4 and 5. 1).

Trametinib monotherapy has not demonstrated clinical activity in patients who have progressed on a prior BRAF inhibitor therapy (see section 5. 1).

* Adjuvant treatment of melanoma:

Trametinib in combination with dabrafenib is indicated for the adjuvant treatment of adult patients with Stage III melanoma with a BRAF V600 mutation, following complete resection.

* Non-small cell lung cancer (NSCLC):

Trametinib in combination with dabrafenib is indicated for the treatment of adult patients with advanced non-small cell lung cancer with a BRAF V600 mutation.

5 Pharmacology and Biochemistry

5.1 Pharmacology

Trametinib is an anticancer agent which causes apoptosis (or programmed cell death) and inhibits cell proliferation, which are both important in the treatment of malignancies.

5.2 MeSH Pharmacological Classification

Antineoplastic Agents

Substances that inhibit or prevent the proliferation of NEOPLASMS. (See all compounds classified as Antineoplastic Agents.)

Protein Kinase Inhibitors

Agents that inhibit PROTEIN KINASES. (See all compounds classified as Protein Kinase Inhibitors.)

5.3 FDA Pharmacological Classification

5.3.1 Active Moiety

TRAMETINIB

5.3.2 FDA UNII

33E86K87QN

5.3.3 Pharmacological Classes

Protein Kinase Inhibitors [MoA]; Kinase Inhibitor [EPC]

5.4 ATC Code

L01EE01

L - Antineoplastic and immunomodulating agents

L01 - Antineoplastic agents

L01E - Protein kinase inhibitors

L01EE - Mitogen-activated protein kinase (mek) inhibitors

L01EE01 - Trametinib

5.5 Absorption, Distribution and Excretion

Absorption

Trametinib is readily absorbed. When an oral administration of trametinib was given to patients with BRAF V600 mutation-positive melanoma, peak plasma concentration occurred 1.5 hours post-dose (Tmax). A single 2 mg oral dose has a bioavailability of 72%. When a dose of 2mg/day is given, the peak plasma concentration (Cmax) is 22.2 ng/mL.

Route of Elimination

80% of the dose is excreted in the feces. <20% of the dose is excreted in the urine with <0.1% of the excreted dose in the form of the parent compound.

Volume of Distribution

Apparent volume of distribution (Vd/F) = 214 L

Clearance

Apparent clearance = 4.9 L/h

5.6 Metabolism/Metabolites

Trametinib is metabolized predominantly via deacetylation alone or with mono-oxygenation or in combination with glucuronidation biotransformation pathways in vitro. Deacetylation is likely mediated by hydrolytic enzymes, such as carboxyl-esterases or amidases. The cytochrome P450 enzyme system is not involved with the metabolism of trametinib. The predominant circulating component in the plasma is the parent drug.

5.7 Biological Half-Life

Elimination half-life = 3.9-4.8 days.

5.8 Mechanism of Action

Trametinib is a reversible, allosteric inhibitor of mitogen-activated extracellular signal regulated kinase 1 _(MEK1)_ and _MEK2_ activation and of_ MEK1_ and _MEK2_ kinase activity. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. Trametinib helps with melanoma with the BRAF V600E or V600K as the mutation results in the constitutive activation of the BRAF pathway which includes MEK1 and MEK2.