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Umbralisib

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21 Drugs in Development

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Synopsis

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Chemistry

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Also known as: 1532533-67-7, Tgr-1202, Rp-5264, Tgr1202, Rp5264, Tgr-1202 free base

Molecular Formula

C₃₁H₂₄F₃N₅O₃

Molecular Weight

571.5 g/mol

InChI Key

IUVCFHHAEHNCFT-INIZCTEOSA-N

FDA UNII

38073MQB2A

Umbralisib is an orally bioavailable, selective inhibitor of the delta isoform of the 110 kDa catalytic subunit of class I phosphoinositide-3 kinases (PI3K) with potential antineoplastic activity. PI3K-delta inhibitor TGR-1202 inhibits PI3K and prevents the activation of the PI3K/AKT kinase signaling pathway. This decreases proliferation and induces cell death in susceptible tumor cells. Unlike other isoforms of PI3K, PI3K-delta is expressed primarily in tumor cells and cells of the hematopoietic lineage. The targeted inhibition of PI3K-delta allows for PI3K signaling in normal, non-neoplastic cells. PI3K, an enzyme often overexpressed in cancer cells, plays a crucial role in tumor cell regulation and survival.

Umbralisib is a Kinase Inhibitor. The mechanism of action of umbralisib is as a Kinase Inhibitor.

1 2D Structure

Umbralisib

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

2-[(1S)-1-[4-amino-3-(3-fluoro-4-propan-2-yloxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-6-fluoro-3-(3-fluorophenyl)chromen-4-one

2.1.2 InChI

InChI=1S/C31H24F3N5O3/c1-15(2)41-24-9-7-18(12-22(24)34)27-26-30(35)36-14-37-31(26)39(38-27)16(3)29-25(17-5-4-6-19(32)11-17)28(40)21-13-20(33)8-10-23(21)42-29/h4-16H,1-3H3,(H2,35,36,37)/t16-/m0/s1

2.1.3 InChI Key

IUVCFHHAEHNCFT-INIZCTEOSA-N

2.1.4 Canonical SMILES

CC(C)OC1=C(C=C(C=C1)C2=NN(C3=NC=NC(=C23)N)C(C)C4=C(C(=O)C5=C(O4)C=CC(=C5)F)C6=CC(=CC=C6)F)F

2.1.5 Isomeric SMILES

C[C@@H](C1=C(C(=O)C2=C(O1)C=CC(=C2)F)C3=CC(=CC=C3)F)N4C5=NC=NC(=C5C(=N4)C6=CC(=C(C=C6)OC(C)C)F)N

2.2 Other Identifiers

2.2.1 UNII

38073MQB2A

2.3 Synonyms

2.3.1 MeSH Synonyms

1. Tgr-1202

2. Ukoniq

2.3.2 Depositor-Supplied Synonyms

1. 1532533-67-7

2. Tgr-1202

3. Rp-5264

4. Tgr1202

5. Rp5264

6. Tgr-1202 Free Base

7. Ukoniq

8. Umbralisib [usan]

9. (s)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1h-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4h-chromen-4-one

10. Tgr 1202

11. Tgr-1202 Base

12. 38073mqb2a

13. 2-[(1s)-1-[4-amino-3-(3-fluoro-4-propan-2-yloxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-6-fluoro-3-(3-fluorophenyl)chromen-4-one

14. 2-((1s)-1-(4-amino-3-(3-fluoro-4-(1-methylethoxy)phenyl)-1h-pyrazolo(3,4-d)pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4h-1-benzopyran-4-one

15. Umbralisib [inn]

16. Umbralisib (usan/inn)

17. Umbralisib [who-dd]

18. Unii-38073mqb2a

19. Gtpl8916

20. Chembl3948730

21. Schembl15557416

22. Tgr 1202 [who-dd]

23. Bdbm184556

24. Dtxsid601337137

25. Bcp24686

26. Ex-a1645

27. Mfcd28386165

28. Nsc793696

29. Nsc800405

30. S8194

31. Example A1 [us2014011819]

32. Zinc141831516

33. Ccg-270101

34. Cs-5243

35. Db14989

36. Nsc-793696

37. Nsc-800405

38. Rp 5264

39. Ac-33183

40. As-52257

41. Hy-12279

42. Us9150579, B1

43. D11322

44. P14656

45. A901657

46. Q27088612

47. (s)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1h-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4h-chromen-4-one;rp-5264

48. 4h-1-benzopyran-4-one, 2-((1s)-1-(4-amino-3-(3-fluoro-4-(1-methylethoxy)phenyl)-1h-pyrazolo(3,4-d)pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-

2.4 Create Date

2014-03-03

3 Chemical and Physical Properties

Molecular Formula	C₃₁H₂₄F₃N₅O₃
Molecular Weight	571.5 g/mol
XLogP3	5.8
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	10
Rotatable Bond Count	6
Exact Mass	571.18312413 g/mol
Monoisotopic Mass	571.18312413 g/mol
Topological Polar Surface Area	105 Å²
Heavy Atom Count	42
Formal Charge	0
Complexity	1020
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

Umbralisib is indicated to treat relapsed or refractory marginal zone lymphoma (MZL) in patients who have received at least one prior anti-CD20-based regimen. It is also indicated for the treatment of relapsed or refractory follicular lymphoma (FL) who have received at least three prior lines of systemic therapy.

5 Pharmacology and Biochemistry

5.1 Pharmacology

Umbralisib acts against against marginal zone lymphoma by interrupting the PI3K pathway; this is an essential pathway for B-cell receptor signaling responsible for the progression of lymphoma. In addition, Umbralisib inhibits other pathways involved in specific types of lymphoma, including the casein kinase pathway. An overall response rate of 55% was recorded during clinical trials and the rate of 1-year progression free survival from marginal zone lymphoma was 71%. A relationship between higher umbralisib steady state exposures and higher incidence of adverse reactions, including diarrhea and elevated AST/ALT was observed during clinical studies. The effect of this drug on QT interval has not been fully characterized.

5.2 FDA Pharmacological Classification

5.2.1 Active Moiety

UMBRALISIB

5.2.2 FDA UNII

38073MQB2A

5.2.3 Pharmacological Classes

Mechanisms of Action [MoA] - Kinase Inhibitors

5.3 Absorption, Distribution and Excretion

Absorption

Umbralisib is rapidly absorbed in the GI tract. The Tmax of umbralisib is about 4 hours. After consumption of a high-fat, high calorie meal with umbralisib, the AUC increased by 61% and the Cmax increased by 115%.

Route of Elimination

During pharmacokinetic studies, about 81% of the umbralisib dose was recovered in feces (17% unchanged). Approximately 3% was detected in the urine (0.02% unchanged) after a radiolabeled dose of 800 mg in healthy volunteers.

Volume of Distribution

The average apparent central volume of distribution of umbralisib is 312 L.

Clearance

The average apparent clearance of umbralisib is 15.5 L/h.

5.4 Metabolism/Metabolites

During in vitro studies, umbralisib was metabolized by CYP2C9, CYP3A4, and CYP1A2 enzymes.

5.5 Biological Half-Life

The effective half-life of Umbralisib is about 91 hours.

5.6 Mechanism of Action

The PI3K pathway is a deregulated in malignancies, leading to the overexpression of p110 isoforms (p110, p110, p110, p110) that induces malignant transformation in cells. Umbralisib inhibits several protein kinases, including PI3K and casein kinase CK1. PI3K is expressed in both healthy cells and malignant B-cells. CK1 is believed to be involved in the pathogenesis of malignant cells, including lymphomas. This results in reduced progression of relapsed or refractory lymphoma. In biochemical assays, umbralisib inhibited a mutated form of ABL1. In vitro, umbralisib inhibits malignant cell proliferation, CXCL12-mediated cell adhesion, and CCL19-mediated cell migration.

Drugs in Development