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Selpercatinib

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Also known as: 2152628-33-4, Loxo-292, Retevmo, Selpercatinib [inn], Cegm9ybngd, Selpercatinib [usan]

Molecular Formula

C₂₉H₃₁N₇O₃

Molecular Weight

525.6 g/mol

InChI Key

XIIOFHFUYBLOLW-UHFFFAOYSA-N

FDA UNII

CEGM9YBNGD

Selpercatinib is an orally bioavailable selective inhibitor of wild-type, mutant and fusion products involving the proto-oncogene receptor tyrosine kinase rearranged during transfection (RET), with potential antineoplastic activity. Upon oral administration, selpercatinib selectively binds to and targets wild-type RET as well as various RET mutants and RET-containing fusion products. This results in an inhibition of cell growth of tumors cells that exhibit increased RET activity. In addition, selpercatinib targets, binds to and inhibits vascular endothelial growth factor receptor 1 (VEGFR1) and 3 (VEGFR3), and fibroblast growth factor receptor 1 (FGFR1), 2 (FGFR2), and 3 (FGFR3). RET overexpression, activating mutations, and fusions result in the upregulation and/or overactivation of RET tyrosine kinase activity in various cancer cell types; dysregulation of RET activity plays a key role in the development and progression of these cancers.

Selpercatinib is a Kinase Inhibitor. The mechanism of action of selpercatinib is as a Rearranged during Transfection (RET) Inhibitor, and Cytochrome P450 2C8 Inhibitor, and Cytochrome P450 3A Inhibitor, and P-Glycoprotein Inhibitor, and Breast Cancer Resistance Protein Inhibitor, and Multidrug and Toxin Extrusion Transporter 1 Inhibitor.

1 2D Structure

Selpercatinib

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

6-(2-hydroxy-2-methylpropoxy)-4-[6-[6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]pyridin-3-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile

2.1.2 InChI

InChI=1S/C29H31N7O3/c1-29(2,37)18-39-24-9-25(28-21(10-30)13-33-36(28)17-24)20-5-6-26(31-12-20)34-15-22-8-23(16-34)35(22)14-19-4-7-27(38-3)32-11-19/h4-7,9,11-13,17,22-23,37H,8,14-16,18H2,1-3H3

2.1.3 InChI Key

XIIOFHFUYBLOLW-UHFFFAOYSA-N

2.1.4 Canonical SMILES

CC(C)(COC1=CN2C(=C(C=N2)C#N)C(=C1)C3=CN=C(C=C3)N4CC5CC(C4)N5CC6=CN=C(C=C6)OC)O

2.2 Other Identifiers

2.2.1 UNII

CEGM9YBNGD

2.3 Synonyms

2.3.1 MeSH Synonyms

1. 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo(3.1.1)heptan-3-yl)pyridin-3-yl)pyrazolo(1,5-a)pyridine-3-carbonitrile

2. Loxo-292

3. Serpercatinib

2.3.2 Depositor-Supplied Synonyms

1. 2152628-33-4

2. Loxo-292

3. Retevmo

4. Selpercatinib [inn]

5. Cegm9ybngd

6. Selpercatinib [usan]

7. Ly3527723

8. Ret Inhibitor Loxo-292

9. Loxo292

10. 6-(2-hydroxy-2-methylpropoxy)-4-[6-[6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]pyridin-3-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile

11. 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

12. Ly-3527723

13. 6-(2-hydroxy-2-methylpropoxy)-4-[6-[6-[(6-methoxy-3-pyridinyl)methyl]-3,6-diazabicyclo[3.1.1]hept-3-yl]-3-pyridinyl]pyrazolo[1,5-a]pyridine-3-carbonitrile

14. 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo(3.1.1)heptan-3-yl)pyridin-3-yl)pyrazolo(1,5-a)pyridine-3-carbonitrile

15. Pyrazolo(1,5-a)pyridine-3-carbonitrile, 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxy-3-pyridinyl)methyl)-3,6-diazabicyclo(3.1.1)hept-3-yl)-3-pyridinyl)-

16. Serpercatinib

17. Retevmo (tn)

18. Unii-cegm9ybngd

19. Selpercatinib [mi]

20. Selpercatinib [jan]

21. Loxo-292; Selpercatinib

22. Selpercatinib(loxo-292)

23. Selpercatinib [who-dd]

24. Chembl4559134

25. Schembl20071478

26. Selpercatinib (jan/usan/inn)

27. Gtpl10318

28. Bdbm296429

29. Dtxsid901026442

30. Selpercatinib [orange Book]

31. Bcp29047

32. Cld62833

33. Ex-a2859

34. Nsc818434

35. S8781

36. Who 10967

37. Zb1574

38. Us10112942, Example 163

39. Us10112942, Example 166

40. Us10112942, Example 183

41. Akos037649115

42. Nsc-818434

43. Ac-31588

44. Bs-16622

45. Loxo-292;loxo 292;loxo292

46. Selpercatinib (loxo-292, Arry-192)

47. Example 163 [wo2018071447a1]

48. Hy-114370

49. Cs-0084279

50. D11713

51. D77980

52. A929273

2.4 Create Date

2018-06-23

3 Chemical and Physical Properties

Molecular Formula	C₂₉H₃₁N₇O₃
Molecular Weight	525.6 g/mol
XLogP3	2.5
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	9
Rotatable Bond Count	8
Exact Mass	525.24883788 g/mol
Monoisotopic Mass	525.24883788 g/mol
Topological Polar Surface Area	112 Å²
Heavy Atom Count	39
Formal Charge	0
Complexity	885
Isotope Atom Count	0
Defined Atom Stereocenter Count	0
Undefined Atom Stereocenter Count	2
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

4 Drug and Medication Information

4.1 Drug Indication

Selpercatinib is indicated for the treatment of _RET_ fusion-positive non-small cell lung cancer in adult patients. Selpercatinib is also indicated for the systemic treatment of advanced or metastatic _RET_-mutant medullary thyroid cancer and for the systemic treatment of _RET_ fusion-positive radioactive iodine-refractory thyroid cancer in both adult and pediatric patients aged 12 and over. Selpercatinib is currently approved for these indications under an accelerated approval scheme and continued approval may be contingent on future confirmatory trials.

FDA Label

Treatment of all conditions included in the category of malignant neoplasms (except haematopoietic and lymphoid tissue neoplasms)

Retsevmo as monotherapy is indicated for the treatment of adults and adolescents 12 years and older with advanced RET-mutant medullary thyroid cancer (MTC)

- advanced RET fusion-positive non-small cell lung cancer (NSCLC) not previously treated with a RET inhibitor

- advanced RET fusion-positive thyroid cancer who require systematic therapy following prior treatment

5 Pharmacology and Biochemistry

5.1 Pharmacology

Selpercatinib exerts anti-tumour activity in specific cancers through inhibition of mutated forms of RET tyrosine kinases. Due to its increased specificity for RET over other tyrosine kinases, selpercatinib is thought to have an improved safety profile compared to other multi-kinase inhibitors. Despite this, selpercatinib treatment is associated with hepatotoxicity, hypertension, QT interval prolongation, hemorrhagic events, risk of impaired wound healing, and embryo-fetal toxicity; some patients may also exhibit hypersensitivity to selpercatinib.

5.2 FDA Pharmacological Classification

5.2.1 Active Moiety

SELPERCATINIB

5.2.2 FDA UNII

CEGM9YBNGD

5.2.3 Pharmacological Classes

Cytochrome P450 2C8 Inhibitors [MoA]; Cytochrome P450 3A Inhibitors [MoA]; Kinase Inhibitor [EPC]; Multidrug and Toxin Extrusion Transporter 1 Inhibitors [MoA]; P-Glycoprotein Inhibitors [MoA]; Rearranged during Transfection (RET) Inhibitors [MoA]; Breast Cancer Resistance Protein Inhibitors [MoA]

5.3 ATC Code

L01EX22

L - Antineoplastic and immunomodulating agents

L01 - Antineoplastic agents

L01E - Protein kinase inhibitors

L01EX - Other protein kinase inhibitors

L01EX22 - Selpercatinib

5.4 Absorption, Distribution and Excretion

Absorption

In patients with locally advanced or metastatic solid tumours receiving 160 mg of selpercatinib twice daily, steady-state was achieved after approximately 7 days, with a C_max of 2,980 (CV 53%) and AUC_0-24h of 51,600 (CV 58%). The absolute bioavailability is between 60 and 82% (mean 73%), and the median t_max is two hours. Food has no apparent effect on the AUC or C_max of selpercatinib. Patients with hepatic impairment display a concomitant increase in AUC_0-INF for mild (7%), moderate (32%), and severe (77%) impairment.

Route of Elimination

Selpercatinib administered as a single 160 mg dose in healthy individuals was primarily recovered in feces (69%, 14% unchanged) and urine (24%, 12% unchanged).

Volume of Distribution

Selpercatinib has an apparent volume of distribution of 191 L; the volume of distribution increases with increasing body weight.

Clearance

Selpercatinib has an apparent clearance of 6L/h; the clearance increases with increasing body weight.

5.5 Metabolism/Metabolites

Selpercatinib is predominantly metabolized in the liver by CYP3A4.

5.6 Biological Half-Life

Selpercatinib has a half-life of 32 hours in healthy individuals.

5.7 Mechanism of Action

Rearranged during transfection (RET) is a transmembrane receptor tyrosine kinase containing extracellular, transmembrane, and intracellular domains whose activity is required for normal kidney and nervous system development. Constitutive RET activation is primarily achieved through chromosomal rearrangements producing 5' fusions of dimerizable domains to the 3' _RET_ tyrosine kinase domain, such as _KIF5B-RET_ and _CCDC6-RET_, resulting in constitutive dimerization and subsequent autophosphorylation. Constitutive activation leads to increased downstream signalling and is associated with tumour invasion, migration, and proliferation. Selpercatinib is a direct RET kinase inhibitor, exhibiting IC₅₀ values between 0.92 and 67.8 nM depending on the exact _RET_ genotype. Information based on natural as well as induced resistance mutations and molecular modelling suggests that selpercatinib directly inhibits RET autophosphorylation by competing with ATP for binding. Various single amino acid mutations at position 810 inhibit selpercatinib binding without significantly altering ATP binding, potentially leading to treatment failures. Selpercatinib is also reported to inhibit other tyrosine kinase receptors, including VEGFR1, VEGFR3, FGFR1, FGFR2, and FGFR3, at clinically relevant concentrations. The significance of these effects is not well studied.

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