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Asciminib

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US Patents

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Chemistry

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Also known as: Abl-001, 1492952-76-7, Abl001, Asciminib free base, Abl001-nx, Nvp-abl001

Molecular Formula

C₂₀H₁₈ClF₂N₅O₃

Molecular Weight

449.8 g/mol

InChI Key

VOVZXURTCKPRDQ-CQSZACIVSA-N

FDA UNII

L1F3R18W77

Asciminib is an orally bioavailable, allosteric Bcr-Abl1 tyrosine kinase inhibitor, with antineoplastic activity. Upon administration, asciminib targets and binds to the myristoyl pocket of the Bcr-Abl1 fusion protein at a location that is distinct from the ATP-binding domain, thereby inhibiting the activity of both wild-type Bcr-Abl and certain mutation forms, including the T315I mutation. This binding results in the inhibition of Bcr-Abl1-mediated proliferation and enhanced apoptosis of Philadelphia chromosome-positive (Ph+) hematological malignancies. The Bcr-Abl1 fusion protein tyrosine kinase is an abnormal enzyme produced by leukemia cells that contain the Philadelphia chromosome.

1 2D Structure

Asciminib

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

N-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide

2.1.2 InChI

InChI=1S/C20H18ClF2N5O3/c21-20(22,23)31-15-3-1-13(2-4-15)26-19(30)12-9-16(17-5-7-25-27-17)18(24-10-12)28-8-6-14(29)11-28/h1-5,7,9-10,14,29H,6,8,11H2,(H,25,27)(H,26,30)/t14-/m1/s1

2.1.3 InChI Key

VOVZXURTCKPRDQ-CQSZACIVSA-N

2.1.4 Canonical SMILES

C1CN(CC1O)C2=C(C=C(C=N2)C(=O)NC3=CC=C(C=C3)OC(F)(F)Cl)C4=CC=NN4

2.1.5 Isomeric SMILES

C1CN(C[C@@H]1O)C2=C(C=C(C=N2)C(=O)NC3=CC=C(C=C3)OC(F)(F)Cl)C4=CC=NN4

2.2 Other Identifiers

2.2.1 UNII

L1F3R18W77

2.3 Synonyms

2.3.1 MeSH Synonyms

1. Abl001

2. Asciminib Hydrochloride

2.3.2 Depositor-Supplied Synonyms

1. Abl-001

2. 1492952-76-7

3. Abl001

4. Asciminib Free Base

5. Abl001-nx

6. Nvp-abl001

7. Asciminib [usan]

8. Scemblix

9. Example 9

10. L1f3r18w77

11. 1492952-76-7 (free Base)

12. (r)-n-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(1h-pyrazol-5-yl)nicotinamide

13. 3-pyridinecarboxamide, N-(4-(chlorodifluoromethoxy)phenyl)-6-((3r)-3-hydroxy-1-pyrrolidinyl)-5-(1h-pyrazol-3-yl)-

14. N-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3r)-3-hydroxypyrrolidin-1-yl]-5-(1h-pyrazol-5-yl)pyridine-3-carboxamide

15. 3-pyridinecarboxamide, N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3r)-3-hydroxy-1-pyrrolidinyl]-5-(1h-pyrazol-3-yl)-

16. Asciminib [inn]

17. Asciminib (abl001)

18. Asciminib (usan/inn)

19. Asciminib [who-dd]

20. Unii-l1f3r18w77

21. Gtpl8962

22. Chembl4208229

23. Schembl15388306

24. Tqp0925

25. Ex-a3030

26. Bdbm50459091

27. Nsc789925

28. S8555

29. Zinc150275965

30. At30330

31. Ccg-269232

32. Compound 1 [pmid: 30137981]

33. Cs-7655

34. Db12597

35. Nsc-789925

36. (r)-n- (4-(chlorodifluoromethoxy)phenyl)- 6-(3- Hydroxypyrrolidin-1- Yl)-5- (1h-pyrazol- 5-yl)nicotinamide

37. Ba166957

38. Bs-15538

39. Hy-104010

40. D11403

41. A910986

42. Q27074535

43. (r)-n-(4-(chloro Difluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(1h-pyrazol-5-yl)nicotinamide

44. (r)-n-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(1h-pyrazol-3-yl)nicotinamide

45. Ay7

46. N-(4-(chlorodifluoromethoxy)phenyl)-6-((3r)-3- Hydroxypyrrolidin-1-yl)-5-(1h-pyrazol-3-yl)pyridine- 3-carboxamide

2.4 Create Date

2013-12-02

3 Chemical and Physical Properties

Molecular Formula	C₂₀H₁₈ClF₂N₅O₃
Molecular Weight	449.8 g/mol
XLogP3	3
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	8
Rotatable Bond Count	6
Exact Mass	449.1066235 g/mol
Monoisotopic Mass	449.1066235 g/mol
Topological Polar Surface Area	103 Å²
Heavy Atom Count	31
Formal Charge	0
Complexity	626
Isotope Atom Count	0
Defined Atom Stereocenter Count	1
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

Asciminib is indicated for the treatment of adult patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase who have been previously treated with 2 tyrosine kinase inhibitors. It is also indicated in the treatment of Ph+ CML in adult patients with the T315I mutation.

Scemblix is indicated for the treatment of adult patients with Philadelphia chromosome positive chronic myeloid leukaemia in chronic phase (Ph+ CML CP) previously treated with two or more tyrosine kinase inhibitors (see section 5. 1).

5 Pharmacology and Biochemistry

5.1 Pharmacology

Asciminib exerts its therapeutic activity by inhibiting an oncogenic protein responsible for the proliferation of CML. It may be administered orally once or twice a day depending on the condition being treated. By increasing the total daily dose 5-fold as compared to standard therapy (80mg daily vs. 400mg daily), it can be used to treat Ph+ CML with the T315I mutation, a typically treatment-resistant variant of the disease. As with many other chemotherapeutic agents, asciminib treatment can result in various forms of myelosuppression, including thrombocytopenia and neutropenia. Patients should receive frequent laboratory monitoring throughout therapy and dose adjustments may be required based on the severity of observed effects. Patients may also experience pancreatic and/or cardiovascular toxicity, both of which require frequent monitoring and may require dose adjustments as per prescribing information.

5.2 ATC Code

L01EA06

L - Antineoplastic and immunomodulating agents

L01 - Antineoplastic agents

L01E - Protein kinase inhibitors

L01EA - Bcr-abl tyrosine kinase inhibitors

L01EA06 - Asciminib

5.3 Absorption, Distribution and Excretion

Absorption

The median T_max of asciminib following oral administration is 2.5 hours. At a dose of 80mg once daily, the steady-state C_max and AUC_tau were 1781 ng/mL and 15112 ng.h/mL, respectively. At a dose of 40mg twice daily, the steady-state C_max and AUC_tau were 793 ng/mL and 5262 ng.h/mL, respectively. At a dose of 200mg twice daily (for treatment of T315I mutants), the steady-state C_max and AUC_tau were 5642 ng/mL and 37547 ng.h/mL, respectively. As compared to the fasted state, the co-administration of asciminib with a high-fat meal decreased the AUC and C_max by 62% and 68%, respectively, and its co-administration with a low-fat meal decreased the AUC and C_max by 30% and 35%, respectively.

Route of Elimination

Asciminib is eliminated via biliary secretion facilitated by breast cancer-resistant protein (BCRP) transporters. Following oral administration, approximately 80% and 11% of an asciminib dose was recovered in the feces and urine, respectively. Unchanged parent drug accounted for 57% of drug material recovered in the feces and 2.5% in the urine.

Volume of Distribution

At steady-state, the apparent volume of distribution of asciminib is 151 L.

Clearance

The total apparent clearance of asciminib is 6.7 L/h at a total daily dose of 80mg and 4.1 L/h at a dose of 200mg twice daily.

5.4 Metabolism/Metabolites

Asciminib is negligibly metabolized, with unchanged parent drug comprising the main drug component in plasma (~93%) and following excretion (~57% in feces). The main circulating metabolites are M30.5, M44, and M29.5, accounting for approximately 5%, 2%, and 0.4% of the total administered dose, respectively. The oxidative metabolism of asciminib is mediated by CYP3A4, and the glucuronidation of asciminib is mediated by UGT2B7 and UGT2B17.

5.5 Biological Half-Life

The terminal elimination half-life asciminib is 5.5 hours when administered at 40mg twice daily and 9.0 hours when administered at 200mg twice daily.

5.6 Mechanism of Action

In most patients with chronic myeloid leukemia (CML), progression of the disease is driven primarily by a translocation of the Philadelphia chromosome that creates an oncogenic fusion gene, _BCR-ABL1_, between the _BCR_ and _ABL1_ genes. This fusion gene produces a resultant fusion protein, BCR-ABL1, which exhibits elevated tyrosine kinase and transforming activities that contribute to CML proliferation. Asciminib is an allosteric inhibitor of the BCR-ABL1 tyrosine kinase. It binds to the myristoyl pocket of the ABL1 portion of the fusion protein and locks it into an inactive conformation, preventing its oncogenic activity.

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