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Also known as: 606143-52-6, Azd6244, Arry-142886, Azd 6244, 5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-n-(2-hydroxyethoxy)-1-methyl-1h-benzimidazole-6-carboxamide, Azd-6244

Molecular Formula

C₁₇H₁₅BrClFN₄O₃

Molecular Weight

457.7 g/mol

InChI Key

CYOHGALHFOKKQC-UHFFFAOYSA-N

FDA UNII

6UH91I579U

Selumetinib is an orally active, small molecule with potential antineoplastic activity. Selumetinib is an ATP-independent inhibitor of mitogen-activated protein kinase kinase (MEK or MAPK/ERK kinase) 1 and 2. MEK 1 and 2 are dual specificity kinases that are essential mediators in the activation of the RAS/RAF/MEK/ERK pathway, are often upregulated in various cancer cells, and are drivers of diverse cellular responses, including proliferation. Inhibition of both MEK1 and 2 by selumetinib prevents the activation of MEK1/2 dependent effector proteins and transcription factors, thereby leading to an inhibition of cellular proliferation in various cancers.

Selumetinib is a Kinase Inhibitor. The mechanism of action of selumetinib is as a Mitogen-Activated Protein Kinase Kinase 1 Inhibitor, and Mitogen-Activated Protein Kinase Kinase 2 Inhibitor.

1 2D Structure

Selumetinib

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide

2.1.2 InChI

InChI=1S/C17H15BrClFN4O3/c1-24-8-21-16-13(24)7-10(17(26)23-27-5-4-25)15(14(16)20)22-12-3-2-9(18)6-11(12)19/h2-3,6-8,22,25H,4-5H2,1H3,(H,23,26)

2.1.3 InChI Key

CYOHGALHFOKKQC-UHFFFAOYSA-N

2.1.4 Canonical SMILES

CN1C=NC2=C1C=C(C(=C2F)NC3=C(C=C(C=C3)Br)Cl)C(=O)NOCCO

2.2 Other Identifiers

2.2.1 UNII

6UH91I579U

2.3 Synonyms

2.3.1 MeSH Synonyms

1. Arry 142886

2. Arry-142886

3. Arry142886

4. Azd 6244

5. Azd-6244

6. Azd6244

2.3.2 Depositor-Supplied Synonyms

1. 606143-52-6

2. Azd6244

3. Arry-142886

4. Azd 6244

5. 5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-n-(2-hydroxyethoxy)-1-methyl-1h-benzimidazole-6-carboxamide

6. Azd-6244

7. Selumetinib (azd6244)

8. Arry 142886

9. Arry-886

10. Azd6244 (selumetinib)

11. 5-((4-bromo-2-chlorophenyl)amino)-4-fluoro-n-(2-hydroxyethoxy)-1-methyl-1h-benzo[d]imidazole-6-carboxamide

12. Koselugo

13. 5-(4-bromo-2-chlorophenylamino)-4-fluoro-n-(2-hydroxyethoxy)-1-methyl-1h-benzo[d]imidazole-6-carboxamide

14. Chembl1614701

15. Chebi:90227

16. 6uh91i579u

17. Nsc741078

18. Ncgc00189073-01

19. Ncgc00189073-02

20. 6-(4-bromo-2-chloroanilino)-7-fluoro-n-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide

21. Dsstox_cid_28870

22. Dsstox_rid_83139

23. Dsstox_gsid_48944

24. 1h-benzimidazole-6-carboxamide, 5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-n-(2-hydroxyethoxy)-1-methyl-

25. 6-[(4-bromo-2-chlorophenyl)amino]-7-fluoro-n-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide

26. Azd 6244;5-((4-bromo-2-chlorophenyl)amino)-4-fluoro-n-(2-hydroxyethoxy)-1-methyl-1h-benzo[d]imidazole-6-carboxamide;6-(4-bromo-2-chlorophenylamino)-7-fluoro-n-(2-hydroxyethoxy)-3-methyl-3h-benzo[d]imidazole-5-carboxamide

27. Cas-606143-52-6

28. Arry142886

29. Selumetinib [usan:inn]

30. Selumetinibum

31. Unii-6uh91i579u

32. 1h-benzimidazole-6-carboxamide, 5-((4-bromo-2-chlorophenyl)amino)-4-fluoro-n-(2-hydroxyethoxy)-1-methyl-

33. 3ew

34. 5-((4-bromo-2-chlorophenyl)amino)-4-fluoro-n-(2-hydroxyethoxy)-1-methyl-1h-benzimidazole-6-carboxamide

35. Selumetinib [mi]

36. Selumetinib [inn]

37. Selumetinib (usan/inn)

38. Selumetinib [usan]

39. Azd6244 - Selumetinib

40. Selumetinib [who-dd]

41. Schembl155456

42. Gtpl5665

43. Selumetinib, Arry-142886

44. Dtxsid3048944

45. Ex-a020

46. Bcpp000367

47. Hms3244g03

48. Hms3244g04

49. Hms3244h03

50. Hms3265k01

51. Hms3265k02

52. Hms3265l01

53. Hms3265l02

54. Hms3654o03

55. Nsc 741o78

56. Bcp01739

57. Tox21_113362

58. Bdbm50355497

59. Mfcd11977472

60. Nsc800882

61. S1008

62. Zinc31773258

63. Akos015904255

64. Tox21_113362_1

65. Bcp9000354

66. Ccg-264774

67. Cs-0059

68. Db11689

69. Ex-8621

70. Nsc-741078

71. Nsc-800882

72. Sb14707

73. Ncgc00189073-07

74. 6-(4-bromo-2-chloro-anilino)-7-fluoro-n-(2-hydroxyethoxy)-3-methyl-benzimidazole-5-carboxamide

75. Ac-25059

76. Am808016

77. Azd6244,selumetinib, Arry-142886

78. Hy-50706

79. Selumetinib (arry142886/azd6244)

80. Azd6244 (selumetinib,arry-142886)

81. Ft-0674552

82. Sw202561-3

83. D09666

84. 143a526

85. Q-101405

86. Q7448840

87. Brd-k57080016-001-01-9

88. 1h-benzimidazole-6-carboxamide, 5-((4-bromo-2-chlorophenyl)amino)-4-fluoro-n-(2- Hydroxyethoxy)-1-methyl-

89. 5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-n-(2-hydroxyethoxy)-1-methyl-1h-1,3-benzodiazole-6-carboxamide

90. 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3h-benzoimidazole-5-carboxylic Acid (2-hydroxy -ethoxy)-amide

91. 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3h-benzoimidazole-5-carboxylic Acid (2-hydroxy-ethoxy)-amide

92. 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3h-benzoimidazole-5-carboxylic Acid(2-hydroxy-ethoxy)-amide

93. 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3h-benzoimidazole-5-carboxylic Acid (2-hydroxyethoxy)-amide

94. 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3h-benzoimidazole-5-carboxylic Acid(2-hydroxyethoxy)-amide

95. 6-(4-bromo-2chloro-phenylamino)-7-fluoro-3-methyl-3h-benzoimidazole-5-carboxylic Acid (2-hydroxy-ethoxy)-amide

2.4 Create Date

2006-10-25

3 Chemical and Physical Properties

Molecular Formula	C₁₇H₁₅BrClFN₄O₃
Molecular Weight	457.7 g/mol
XLogP3	3.6
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	6
Rotatable Bond Count	6
Exact Mass	456.00001 g/mol
Monoisotopic Mass	456.00001 g/mol
Topological Polar Surface Area	88.4 Å²
Heavy Atom Count	27
Formal Charge	0
Complexity	523
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

Although selumetinib has been investigated for the treatment of several types of cancer, it is currently only indicated for the treatment of neurofibromatosis type 1 (NF1) in patients 2 years who have symptomatic, inoperable plexiform neurofibromas (PN).

FDA Label

Koselugo as monotherapy is indicated for the treatment of symptomatic, inoperable plexiform neurofibromas (PN) in paediatric patients with neurofibromatosis type 1 (NF1) aged 3 years and above

5 Pharmacology and Biochemistry

5.1 Pharmacology

Selumetinib is a non-ATP-competitive mitogen-activated protein kinase kinase 1 and 2 (MEK1 and MEK2) inhibitor. By selectively targeting MEK1 and MEK2, selumetinib is able to inhibit oncogenic downstream effects of the Raf-MEK-ERK signaling pathway, which is often overactive in certain types of cancer. Indeed, a study investigating the effects of selumetinib in children with NF-1 found that treatment with the anti-neoplastic resulted in reduced tumor size. Decreases in tumor-associated pain and improvements in overall function were also subjectively reported. Selumetinib has minimal off-target activity, contributing to its impressive safety profile.

5.2 FDA Pharmacological Classification

5.2.1 Active Moiety

SELUMETINIB

5.2.2 FDA UNII

6UH91I579U

5.2.3 Pharmacological Classes

Mitogen-Activated Protein Kinase Kinase 1 Inhibitors [MoA]; Mitogen-Activated Protein Kinase Kinase 2 Inhibitors [MoA]; Kinase Inhibitor [EPC]

5.3 ATC Code

L - Antineoplastic and immunomodulating agents

L01 - Antineoplastic agents

L01E - Protein kinase inhibitors

L01EE - Mitogen-activated protein kinase (mek) inhibitors

L01EE04 - Selumetinib

5.4 Absorption, Distribution and Excretion

Absorption

Based on several studies investigating selumetinib at various doses in both pediatric and adult populations, the Tmax generally ranges between 1- 1.5 hours. In healthy adults, the mean absolute oral bioavailability was reported to be 62%. Selumetinib should be administered on an empty stomach since food significantly decreases serum concentrations of the drug.

Route of Elimination

Approximately 59% of selumetinib is eliminated in the feces, while 33% is eliminated in the urine.

Volume of Distribution

The mean apparent volume of distribution of selumetinib at steady state in pediatric patients ranged from 78 L to 171 L. A study in healthy adult males found a mean apparent volume of distribution of 146 L. Another study observing the pharmacokinetic effects of various selumetinib doses and regimens in select Japanese patients found that the apparent volume of distribution values at steady-state ranged from 73.2 - 148.1 L.

Clearance

The clearance of selumetinib in pediatric patients is 8.8 L/hr. A study in healthy adult males found a clearance value of 15.7 L/hr. Another study observing the pharmacokinetic effects of various selumetinib doses and regimens in select Japanese patients found clearance values that ranged from 9.2 - 15.9 L/hr.

5.5 Metabolism/Metabolites

Selumetinib is heavily metabolized in the liver and the proposed metabolic pathway is as follows: Hydrolysis of selumetinibs amide functional group produces M15 (AZ13326637), which contains a carboxylic acid. Elimination of the ethanediol moiety from the parent compound results in the formation of the primary amide M14 (AZ12791138) metabolite. Amide hydrolysis transforms M14 into M15, glucuronidation and further oxidation of M14 leads to M2, M6 and M1, and N-demethylation of M14 produces M12. The amide glucuronide (M2) is thought to be the major circulating metabolite. Demethylation of selumetinib produces the pharmacologically active M8 (AZ12442942), and further oxidation of M8 leads to M11. Glucuronidation of M8 produces M3 or M5, and elimination of the ethanediol moiety from M8 results in a primary amide, producing M12. Although the N-demethylated metabolite (M8) accounts for <10% of the circulating metabolites, it is responsible for approximately 21-35% of any observed pharmacological activity. Ribose conjugation transforms M12 into M9, while oxidation of M12 leads to M10 and M13 metabolites. Glucuronidation of M10 produces M1. Direct glucuronidation of selumetinib produces M4 or M7, which can both eventually transform into M3 and M5 metabolites.

5.6 Biological Half-Life

Selumetinib is characterized by a short half-life. The elimination half-life associated with a dose of 25 mg/m² in pediatric patients is 6.2 hours. In a study observing the pharmacokinetic effects of various selumetinib regimens in select Japanese patients, the half-life ranged from 9.2- 10.6 hours. In other studies where selumetinib 75 mg is administered twice daily, the half-life is reported to be approximately 13 hours.

5.7 Mechanism of Action

The Ras-Raf-MEK-ERK signaling cascade is known to be activated in several types of cancer, and regulates the transcription of proteins involved in apoptosis. In addition, studies have shown that mutations of the Raf component of the pathway can contribute to chemotherapy drug resistance. Ras as well as several kinases and phosphatases are responsible for regulating the Raf-MEK-ERK pathway. Often in cancers, Ras (a G-protein coupled receptor) is deregulated, allowing downstream signalling to proceed unchecked. Through several complex steps, Raf phosphorylates and activates MEK, which then phosphorylates and activates ERK. ERK is then able to exert its effects on several downstream targets. As such, therapies inhibiting upstream components of this pathway have become attractive targets for cancer treatment. Selumetinib exerts its effects by selectively inhibiting MEK1 and MEK2 which can effectively blunt the pleiotropic effects of the Ras-Raf-MEK-ERK cascade. By inhibiting this oncogenic pathway, selumetinib reduces cell proliferation, and promotes pro-apoptotic signal transduction.

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