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Tirbanibulin

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US Patents

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Chemistry

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Also known as: Kx2-391, 897016-82-9, Tirbanibulin, Kx-01, Klisyri, Kx-2-391

Molecular Formula

C₂₆H₂₉N₃O₃

Molecular Weight

431.5 g/mol

InChI Key

HUNGUWOZPQBXGX-UHFFFAOYSA-N

FDA UNII

4V9848RS5G

Tirbanibulin is an orally bioavailable small molecule Src kinase inhibitor with potential antineoplastic activity. Unlike other Src kinase inhibitors which bind to the ATP-binding site, tirbanibulin specifically binds to the peptide substrate binding site of Src kinase; inhibition of kinase activity may result in the inhibition of primary tumor growth and the suppression of metastasis. Src tyrosine kinases are upregulated in many tumor cells and play important roles in tumor cell proliferation and metastasis.

Tirbanibulin is a Microtubule Inhibitor. The physiologic effect of tirbanibulin is by means of Microtubule Inhibition.

1 2D Structure

Tirbanibulin

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

N-benzyl-2-[5-[4-(2-morpholin-4-ylethoxy)phenyl]pyridin-2-yl]acetamide

2.1.2 InChI

InChI=1S/C26H29N3O3/c30-26(28-19-21-4-2-1-3-5-21)18-24-9-6-23(20-27-24)22-7-10-25(11-8-22)32-17-14-29-12-15-31-16-13-29/h1-11,20H,12-19H2,(H,28,30)

2.1.3 InChI Key

HUNGUWOZPQBXGX-UHFFFAOYSA-N

2.1.4 Canonical SMILES

C1COCCN1CCOC2=CC=C(C=C2)C3=CN=C(C=C3)CC(=O)NCC4=CC=CC=C4

2.2 Other Identifiers

2.2.1 UNII

4V9848RS5G

2.3 Synonyms

2.3.1 MeSH Synonyms

1. Klisyri

2. Kx-01

3. Kx2-391

4. N-benzyl-2-(5-(4-(2-(4-morpholinyl)ethoxy)phenyl)-2-pyridinyl)acetamide

5. Tirbanibulin

2.3.2 Depositor-Supplied Synonyms

1. Kx2-391

2. 897016-82-9

3. Tirbanibulin

4. Kx-01

5. Klisyri

6. Kx-2-391

7. Kx-2391

8. Kx01

9. Tirbanibulin [usan]

10. Kx2391

11. Chembl571546

12. 4v9848rs5g

13. Kx2-391;kx-01

14. 2-pyridineacetamide, 5-(4-(2-(4-morpholinyl)ethoxy)phenyl)-n-(phenylmethyl)-

15. N-benzyl-2-[5-[4-(2-morpholin-4-ylethoxy)phenyl]pyridin-2-yl]acetamide

16. 2-[5-[4-(2-morpholin-4-ylethoxy)phenyl]pyridin-2-yl]-~{n}-(phenylmethyl)ethanamide

17. Unii-4v9848rs5g

18. N-benzyl-2-(5-(4-(2-morpholin-4-ylethoxy)phenyl)pyridin-2-yl)acetamide

19. Kx 01

20. Tirbanibulin (usan/inn)

21. Tirbanibulin [inn]

22. Kx2-391 (tirbanibulin)

23. Tirbanibulin (kx2-391)

24. Mls006011272

25. Schembl153779

26. Tirbanibulin [who-dd]

27. Gtpl7957

28. Dtxsid30237862

29. Hms3656j15

30. Hms3673e15

31. Tirbanibulin [orange Book]

32. Bcp02845

33. Ex-a2434

34. Xkb01682

35. Bdbm50303801

36. Nsc756643

37. Nsc800779

38. S2700

39. Who 10864

40. Zinc43152787

41. N-benzyl-2-(5-{4-[2-(morpholin-4-yl)ethoxy]phenyl}pyridin-2-yl)acetamide

42. Bcp9000828

43. Ccg-264983

44. Cs-0248

45. Db06137

46. Kx2-391; Kx-01

47. Nsc-756643

48. Nsc-800779

49. Sb16619

50. Ncgc00346644-01

51. Ncgc00346644-05

52. Ac-35458

53. As-73245

54. Hy-10340

55. Kx 2-391

56. Smr004703022

57. Db-119272

58. Sw219670-1

59. C77028

60. D11691

61. A915990

62. Brd-k29968218-001-01-6

63. Q27888424

64. 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-n-benzylacetamide

65. 2-(5-(4-(2-morpholinoethoxyl)phenyl)pyridin-2-yl)-n-benzylacetamide

66. 2-[5-[4-(2-morpholin-4-ylethoxy)phenyl]pyridin-2-yl]-n-(phenylmethyl)acetamide

67. 2-pyridineacetamide,5-[4-[2-(4-morpholinyl)ethoxy]phenyl]-n-(phenylmethyl)-

68. 5-[4-[2-(4-morpholinyl)ethoxy]phenyl]-n-(phenylmethyl)-2-pyridineacetamide

69. Dn0

2.4 Create Date

2008-01-07

3 Chemical and Physical Properties

Molecular Formula	C₂₆H₂₉N₃O₃
Molecular Weight	431.5 g/mol
XLogP3	2.9
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	5
Rotatable Bond Count	9
Exact Mass	431.22089180 g/mol
Monoisotopic Mass	431.22089180 g/mol
Topological Polar Surface Area	63.7 Å²
Heavy Atom Count	32
Formal Charge	0
Complexity	540
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

Tirbanibulin is indicated for the topical treatment of actinic keratosis on the face or scalp.

Klisyri is indicated for the field treatment of non-hyperkeratotic, non-hypertrophic actinic keratosis (Olsen grade 1) of the face or scalp in adults.

5 Pharmacology and Biochemistry

5.1 Pharmacology

In clinical trials composed comprising patients with actinic keratosis of the face or scalp, tirbanibulin promoted complete clearance of actinic keratosis lesions at day 57 in treated areas in 44-54% of patients compared to 5-13% of patients who received the placebo. Actinic keratosis is a chronic, pre-malignant condition characterized by lesions and proliferation of neoplastic keratinocytes. Tirbanibulin mediates an anti-proliferative effect by inhibiting tubulin polymerization and Src kinase signalling. Tirbanibulin inhibited primary tumour growth and metastasis in many preclinical animal models of cancer. In human triple-negative breast cancer, or estrogen receptor (ER)/progesterone receptor (PR)/human epidermal growth factor receptor 2 (HER2)-negative tumour, xenografts, tirbanibulin suppressed tumour growth and metastasis. Tirbanibulin was also shown to restore functional ER expression in ER-negative breast tumours. Tirbanibulin promoted synergistic tumour growth inhibition of breast cancer cell lines when used in combination with tamoxifen and paclitaxel. In a clinical trial comprising patients with advanced solid tumours, dose-limiting toxicities of tirbanibulin included elevated liver transaminases, neutropenia and fatigue.

5.2 MeSH Pharmacological Classification

Enzyme Inhibitors

Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. (See all compounds classified as Enzyme Inhibitors.)

5.3 FDA Pharmacological Classification

5.3.1 Active Moiety

TIRBANIBULIN

5.3.2 FDA UNII

4V9848RS5G

5.3.3 Pharmacological Classes

Established Pharmacologic Class [EPC] - Microtubule Inhibitor

5.4 ATC Code

D06BX03

D - Dermatologicals

D06 - Antibiotics and chemotherapeutics for dermatological use

D06B - Chemotherapeutics for topical use

D06BX - Other chemotherapeutics

D06BX03 - Tirbanibulin

5.5 Absorption, Distribution and Excretion

Absorption

Tirbanibulin demonstrates good oral bioavailability. Following topical administration of doses ranging from 54 to 295 mg on the face or scalp, the steady-state concentration of tirbanibulin was achieved by 72 hours. At five days following initial administration, the mean C_max was 0.340.30 ng/mL in subjects who received topical treatment on the face and 0.180.10 ng/mL in subjects who received topical treatment on the scalp. The mean AUC₂₄ was 5.03.9 h x ng/mL in subjects who received topical treatment on the face and 3.21.9 h x ng/mL in subjects who received topical treatment on the scalp. The median T_max was about seven hours.

Route of Elimination

There is limited information on the route of elimination of tirbanibulin.

Volume of Distribution

There is limited information on the volume of distribution of tirbanibulin. In mouse HT29 xenograft studies, the tissue to plasma ration of tirbanibulin was 1.52.

Clearance

There is limited information on the clearance rate of tirbanibulin.

5.6 Metabolism/Metabolites

_In vitro_, tirbanibulin is mainly metabolized by CYP3A4, and to a lesser extent, CYP2C8. In adult subjects with actinic keratosis, detected metabolites were KX2-5036 and KX2-5163, which were pharmacologically inactive metabolites with the highest plasma concentrations of 0.09 ng/mL and 0.12 ng/mL, respectively.

5.7 Biological Half-Life

The half-life is about 4 hours.

5.8 Mechanism of Action

Src tyrosine kinases regulate normal cell growth: the expression of Src kinase is upregulated during the normal hair cycle during the proliferative anagen phase. Additionally, Src tyrosine kinases act as key modulators of cancer cell proliferation, survival, angiogenesis, migration, invasion and metastasis. Src is frequently upregulated in various epithelial tumours including colon, breast and pancreas compared with the adjacent normal tissues. The expression and activity of Src are also enhanced in human actinic keratosis, which is characterized by hyperproliferative premalignant skin lesions. The pathogenesis of actinic keratosis commonly involves skin inflammation, oxidative stress, immunosuppression, impaired apoptosis, mutagenesis, dysregulation of keratinocyte growth and proliferation, and tissue remodelling. _In vitro_ studies suggest that Src plays a predominant role in the early stages of human skin tumour development, rather than at later stages of tumour progression. The exact mechanism of tirbanibulin as a topical treatment of actinic keratosis has not been fully elucidated; however, it mainly works by inhibiting fast proliferating cells. Tirbanibulin is a non-ATP competitive Src kinase inhibitor and tubulin polymerization inhibitor. It binds to the peptide substrate binding site of Src, a primary target of tirbanibulin, and blocking its downstream signalling pathways that promote cancer cell migration, proliferation, and survival. Tublin is responsible for cell migration, protein transport, and mitosis: tibranibulin directly binds to the colchicine-binding site of beta-tubulin and causes induces tubulin depolymerization. It is also hypothesized that inhibition of Src can also contribute to the inhibitory effects on microtubule polymerization. At low nanomolar concentrations, tirbanibulin induces G2/M phase cell cycle arrest in a reversible and dose-dependent manner. By inhibiting microtubule polymerization, tirbanibulin also induces mitotic catastrophe.

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