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Entrectinib

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Chemistry

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Also known as: 1108743-60-7, Rxdx-101, Nms-e628, Rozlytrek, Entrectinib (rxdx-101), Entrectinib(rxdx-101)

Molecular Formula

C₃₁H₃₄F₂N₆O₂

Molecular Weight

560.6 g/mol

InChI Key

HAYYBYPASCDWEQ-UHFFFAOYSA-N

FDA UNII

L5ORF0AN1I

Entrectinib is an orally bioavailable inhibitor of the tyrosine kinases tropomyosin receptor kinases (Trk) A, B and C, C-ros oncogene 1 (ROS1) and anaplastic lymphoma kinase (ALK), with potential antineoplastic activity. Upon administration, entrectinib binds to and inhibits TrkA, TrkB, TrkC, ROS1 and ALK. Inhibition of these kinases may result in a disruption of TrkA-, TrkB-, TrkC-, ROS1-, and ALK-mediated signaling. This leads to an induction of apoptosis and an inhibition of tumor cell proliferation in tumor cells that express these kinases. TrkA, TrkB, TrkC, ROS1 and ALK are overexpressed in a variety of cancer cell types.

1 2D Structure

Entrectinib

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-(oxan-4-ylamino)benzamide

2.1.2 InChI

InChI=1S/C31H34F2N6O2/c1-38-8-10-39(11-9-38)25-3-4-26(29(19-25)34-24-6-12-41-13-7-24)31(40)35-30-27-17-20(2-5-28(27)36-37-30)14-21-15-22(32)18-23(33)16-21/h2-5,15-19,24,34H,6-14H2,1H3,(H2,35,36,37,40)

2.1.3 InChI Key

HAYYBYPASCDWEQ-UHFFFAOYSA-N

2.1.4 Canonical SMILES

CN1CCN(CC1)C2=CC(=C(C=C2)C(=O)NC3=NNC4=C3C=C(C=C4)CC5=CC(=CC(=C5)F)F)NC6CCOCC6

2.2 Other Identifiers

2.2.1 UNII

L5ORF0AN1I

2.3 Synonyms

2.3.1 MeSH Synonyms

1. N-(5-(3,5-difluorobenzyl)-1h-indazol-3-yl)-4-(4-methyl-1-piperazinyl)-2-(tetrahydro-2h-pyran-4-ylamino)benzamide

2. Nms-e628

3. Rozlytrek

4. Rxdx-101

2.3.2 Depositor-Supplied Synonyms

1. 1108743-60-7

2. Rxdx-101

3. Nms-e628

4. Rozlytrek

5. Entrectinib (rxdx-101)

6. Entrectinib(rxdx-101)

7. L5orf0an1i

8. N-(5-(3,5-difluorobenzyl)-1h-indazol-3-yl)-4-(4-methylpiperazin-1-yl)-2-((tetrahydro-2h-pyran-4-yl)amino)benzamide

9. Benzamide, N-(5-((3,5-difluorophenyl)methyl)-1h-indazol-3-yl)-4-(4-methyl-1-piperazinyl)-2-((tetrahydro-2h-pyran-4-yl)amino)-

10. N-(5-(3,5-difluorobenzyl)-1h-indazol-3-yl)-4-(4-methylpiperazin-1yl)-2-(tetrahydro-2h-pyran-4-ylamino)benzamide

11. N-[5-[(3,5-difluorophenyl)methyl]-1h-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-(oxan-4-ylamino)benzamide

12. Benzamide, N-[5-[(3,5-difluorophenyl)methyl]-1h-indazol-3-yl]-4-(4-methyl-1-piperazinyl)-2-[(tetrahydro-2h-pyran-4-yl)amino]-

13. N-{5-[(3,5-difluorophenyl)methyl]-1h-indazol-3-yl}-4-(4-methylpiperazin-1-yl)-2-[(oxan-4-yl)amino]benzamide

14. Entrectinib [inn]

15. Unii-l5orf0an1i

16. Entrectinib [usan:inn]

17. Rozlytrek (tn)

18. Ymx

19. Entrectinib, 95%

20. Kinome_2659

21. Entrectinib [mi]

22. Entrectinib [jan]

23. Entrectinib; Nms-e628

24. Entrectinib [usan]

25. Entrectinib [who-dd]

26. Entrectinib (jan/usan/inn)

27. Gtpl8290

28. Schembl3512601

29. Chembl1983268

30. Nms-e-628

31. Entrectinib [orange Book]

32. Nms-e628;rxdx-101

33. Dtxsid101026450

34. Hms3886h21

35. Bcp16174

36. Ex-a2261

37. Mfcd28129099

38. Nsc774769

39. Nsc800095

40. S7998

41. Zinc43204146

42. Ccg-270048

43. Db11986

44. Nsc-774769

45. Nsc-800095

46. Sb17194

47. Ncgc00484067-01

48. Ncgc00484067-02

49. Ncgc00484067-03

50. Ac-31286

51. As-75092

52. Da-47850

53. Hy-12678

54. B5859

55. Ft-0736318

56. D10926

57. A856078

58. Q25323953

59. S900006830

60. Rxdx101; Rxdx 101; Rxdx-101; Nms E628; Nms-e628;nms E628

61. N-(5-(3,5-difluorobenzyl)-1h-indazol-3-yl)-4-(4-methyl-1-piperazinyl)-2-(tetrahydro-2h-pyran-4-ylamino)benzamide

62. N-(5-(3,5-difluorobenzyl)-1h-indazol-3-yl)-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-2h-pyran-4-ylamino)benzamide

63. N-[5-(3,5-difluoro-benzyl)-1h-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide

64. N-{5-[(3,5-difluorophenyl)methyl]-3h-indazol-3-ylidene}-4-(4-methylpiperazin-1-yl)-2-[(oxan-4-yl)amino]benzamide

2.4 Create Date

2009-02-09

3 Chemical and Physical Properties

Molecular Formula	C₃₁H₃₄F₂N₆O₂
Molecular Weight	560.6 g/mol
XLogP3	5.7
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	8
Rotatable Bond Count	7
Exact Mass	560.27113067 g/mol
Monoisotopic Mass	560.27113067 g/mol
Topological Polar Surface Area	85.5 Å²
Heavy Atom Count	41
Formal Charge	0
Complexity	847
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

Entrectinib is indicated for the treatment of metastatic ROS1-positive non-small cell lung cancer in adults. Entrectinib is also indicated in adults and children over 12 years old for the treatment of NTRK gene fusion-positive solid tumors which have metastasized or for which surgical resection is likely to result in severe morbidity and for which has progressed on previous therapies or for which no comparable alternative therapies are available.

FDA Label

Rozlytrek as monotherapy is indicated for the treatment of adult and paediatric patients 12 years of age and older with solid tumours expressing a neurotrophic tyrosine receptor kinase (NTRK) gene fusion,

- who have a disease that is locally advanced, metastatic or where surgical resection is likely to result in severe morbidity, and

- who have not received a prior NTRK inhibitor

- who have no satisfactory treatment options.

Rozlytrek as monotherapy is indicated for the treatment of adult patients with ROS1 positive, advanced non small cell lung cancer (NSCLC) not previously treated with ROS1 inhibitors.

5 Pharmacology and Biochemistry

5.1 Pharmacology

Entrectinib and its active metabolite suppress several pathways which contribute to cell survival and proliferation. This suppression shifts the balance in favor of apoptosis thereby preventing cancer cell growth and shrinking tumors.

5.2 MeSH Pharmacological Classification

Protein Kinase Inhibitors

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

5.3 ATC Code

L01EX14

L - Antineoplastic and immunomodulating agents

L01 - Antineoplastic agents

L01E - Protein kinase inhibitors

L01EX - Other protein kinase inhibitors

L01EX14 - Entrectinib

5.4 Absorption, Distribution and Excretion

Absorption

Entrectinib has a Tmax of 4-5 h after administration of a single 600 mg dose. Food does not produce a significant effect on the extent of absorption.

Route of Elimination

After a single radio-labeled dose of entrectinib, 83% of radioactivity was present in the feces and 3% in the urine. Of the dose in the feces, 36% was present as entrectinib and 22% as M5.

Volume of Distribution

Entrectinib has an apparent volume of distribution of 551 L. The active metabolite, M5, has an apparent volume of distribution of 81.1 L. Entrectinib is known to cross the blood-brain barrier.

Clearance

The apparent clearance of entrectinib is 19.6 L/h while the apparent clearance of the active metabolite M5 is 52.4 L/h.

5.5 Metabolism/Metabolites

CYP3A4 is responsible for 76% of entrectinib metabolism in humans including metabolism to the active metabolite, M5. M5 has similar pharmacological activity to entrectinib and exists at approximately 40% of the steady state concentration of the parent drug. In rats, six in vivo metabolites have been identified including N-dealkylated, N-oxide, hydroxylated, and glucuronide conjugated metabolites.

5.6 Biological Half-Life

Entrectinib has a half-life of elimination of 20 h. The active metabolite, M5, has a half-life of 40 h.

5.7 Mechanism of Action

Entrectinib is a tyrosine kinase inhibitor which acts on several receptors. It functions as an ATP competitor to inhibit tropomyosin receptor tyrosine kinases (TRK) TRKA, TRKB, TRKC, as well as proto-oncogene tyrosine-protein kinase ROS1 and anaplastic lymphoma kinase (ALK). TRK receptors produce cell proliferation via downstream signalling through the mitogen activated protein kinase, phosphoinositide 3-kinase, and phospholipase C-. ALK produces similar signalling with the addition of downstream JAK/STAT activation. Inhibition of these pathways suppresses cancer cell proliferation and shifts the balance in favor of apoptosis resulting in shrinking of tumor volume.

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