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    Trilaciclib

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    2D Structure
    Also known as: 1374743-00-6, G1t28, Cosela, Trilaciclib [usan], U6072do9xg, 2'-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-7',8'-dihydro-6'h-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one
    Molecular Formula
    C24H30N8O
    Molecular Weight
    446.5  g/mol
    InChI Key
    PDGKHKMBHVFCMG-UHFFFAOYSA-N
    FDA UNII
    U6072DO9XG
    Trilaciclib is a small molecule, competitive inhibitor of cyclin dependent kinases 4 and 6 (CDK4/6), with potential antineoplastic and chemoprotective activities. Upon intravenous administration, trilaciclib binds to and inhibits the activity of CDK4/6, thereby blocking the phosphorylation of the retinoblastoma protein (Rb) in early G1. This prevents G1/S phase transition, causes cell cycle arrest in the G1 phase, induces apoptosis, and inhibits the proliferation of CDK4/6-overexpressing tumor cells. In patients with CDK4/6-independent tumor cells, G1T28 may protect against multi-lineage chemotherapy-induced myelosuppression (CIM) by transiently and reversibly inducing G1 cell cycle arrest in hematopoietic stem and progenitor cells (HSPCs) and preventing transition to the S phase. This protects all hematopoietic lineages, including red blood cells, platelets, neutrophils and lymphocytes, from the DNA-damaging effects of certain chemotherapeutics and preserves the function of the bone marrow and the immune system. CDKs are serine/threonine kinases involved in the regulation of the cell cycle and may be overexpressed in certain cancer cell types. HSPCs are dependent upon CDK4/6 for proliferation.
    Trilaciclib is a Kinase Inhibitor. The mechanism of action of trilaciclib is as a Cyclin-dependent Kinase 4 Inhibitor, and Cyclin-dependent Kinase 6 Inhibitor, and Organic Cation Transporter 2 Inhibitor, and Multidrug and Toxin Extrusion Transporter 1 Inhibitor, and Multidrug and Toxin Extrusion Transporter 2 K Inhibitor.
    1 2D Structure

    2D Structure

    2 Identification
    2.1 Computed Descriptors
    2.1.1 IUPAC Name
    4-[[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino]spiro[1,3,5,11-tetrazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraene-13,1'-cyclohexane]-10-one
    2.1.2 InChI
    InChI=1S/C24H30N8O/c1-30-9-11-31(12-10-30)18-5-6-20(25-15-18)28-23-26-14-17-13-19-22(33)27-16-24(7-3-2-4-8-24)32(19)21(17)29-23/h5-6,13-15H,2-4,7-12,16H2,1H3,(H,27,33)(H,25,26,28,29)
    2.1.3 InChI Key
    PDGKHKMBHVFCMG-UHFFFAOYSA-N
    2.1.4 Canonical SMILES
    CN1CCN(CC1)C2=CN=C(C=C2)NC3=NC=C4C=C5C(=O)NCC6(N5C4=N3)CCCCC6
    2.2 Other Identifiers
    2.2.1 UNII
    U6072DO9XG
    2.3 Synonyms
    2.3.1 MeSH Synonyms

    1. 2'-((5-(4-methyl-1-piperazinyl)-2-pyridinyl)amino)-7',8'-dihydro-6'h-spiro(cyclohexane-1,9'-pyrazino(1',2':1,5)pyrrolo(2,3-d)pyrimidin)-6'-one

    2. Cosela

    3. Spiro(cyclohexane-1,9'(6'h)-pyrazino(1',2':1,5)pyrrolo(2,3-d)pyrimidin)-6'-one, 7',8'-dihydro-2'-((5-(4-methyl-1-piperazinyl)-2-pyridinyl)amino)-

    2.3.2 Depositor-Supplied Synonyms

    1. 1374743-00-6

    2. G1t28

    3. Cosela

    4. Trilaciclib [usan]

    5. U6072do9xg

    6. 2'-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-7',8'-dihydro-6'h-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one

    7. Spiro(cyclohexane-1,9'(6'h)-pyrazino(1',2':1,5)pyrrolo(2,3-d)pyrimidin)-6'-one, 7',8'-dihydro-2'-((5-(4-methyl-1-piperazinyl)-2-pyridinyl)amino)-

    8. 2'-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-7',8'-dihydro-6'h-spiro(cyclohexane-1,9'-pyrazino(1',2':1,5)pyrrolo(2,3-d)pyrimidin)-6'-one

    9. G1t28(trilaciclib)

    10. G1t28 Di-hcl

    11. Trilaciclib [inn]

    12. Trilaciclib (usan/inn)

    13. Unii-u6072do9xg

    14. Trilaciclib [who-dd]

    15. Gtpl9626

    16. Chembl3894860

    17. Schembl10082028

    18. Bdbm253928

    19. Dtxsid601337125

    20. Bcp25013

    21. Ex-a4297

    22. Nsc816987

    23. Db15442

    24. Nsc-816987

    25. Sb19783

    26. Ac-36547

    27. Us9464092, T

    28. Hy-101467

    29. Cs-0021431

    30. A17084

    31. D11130

    32. 2'-((5-(4-methyl-1-piperazinyl)-2-pyridinyl)amino)-7',8'-dihydro-6'h-spiro(cyclohexane-1,9'-pyrazino(1',2':1,5)pyrrolo(2,3-d)pyrimidin)-6'-one

    33. 2'-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-7',8'-dihydro-6'hspiro(cyclohexane-1,9'-pyrazino(1',2':1,5)pyrrolo(2,3-d)pyrimidin)-6'-one

    34. 2-[[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino]spiro[7,8-dihydropyrazino[5,6]pyrrolo[1,2-d]pyrimidine-9,1'-cyclohexane]-6-one

    35. 4-[[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino]spiro[1,3,5,11-tetrazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraene-13,1'-cyclohexane]-10-one

    2.4 Create Date
    2012-11-30
    3 Chemical and Physical Properties
    Molecular Weight 446.5 g/mol
    Molecular Formula C24H30N8O
    XLogP32.6
    Hydrogen Bond Donor Count2
    Hydrogen Bond Acceptor Count7
    Rotatable Bond Count3
    Exact Mass446.25425761 g/mol
    Monoisotopic Mass446.25425761 g/mol
    Topological Polar Surface Area91.2 Ų
    Heavy Atom Count33
    Formal Charge0
    Complexity707
    Isotope Atom Count0
    Defined Atom Stereocenter Count0
    Undefined Atom Stereocenter Count0
    Defined Bond Stereocenter Count0
    Undefined Bond Stereocenter Count0
    Covalently Bonded Unit Count1
    4 Drug and Medication Information
    4.1 Drug Indication

    Trilaciclib is indicated to reduce the incidence of chemotherapy induced myelosuppression in patients prior to receiving platinum and etoposide-containing or topotecan-containing chemotherapy regimens for extensive-stage small cell lung cancer.

    5 Pharmacology and Biochemistry
    5.1 Pharmacology

    Trilaciclib is indicated to reduce the incidence of chemotherapy induced myelosuppression in patients prior to receiving platinum and etoposide-containing or topotecan-containing chemotherapy regimens for extensive-stage small cell lung cancer. It has a short duration of action of approximately 16 hours, and a narrow therapeutic index. Patients should be counselled regarding the risk of injection site reactions, hypersensitivity, and interstitial lung disease.

    5.2 FDA Pharmacological Classification
    5.2.1 Active Moiety
    TRILACICLIB
    5.2.2 FDA UNII
    U6072DO9XG
    5.2.3 Pharmacological Classes
    Mechanisms of Action [MoA] - Multidrug and Toxin Extrusion Transporter 2 K Inhibitors
    5.3 ATC Code

    V - Various

    V03 - All other therapeutic products

    V03A - All other therapeutic products

    V03AF - Detoxifying agents for antineoplastic treatment

    V03AF12 - Trilaciclib

    5.4 Absorption, Distribution and Excretion

    Absorption

    Cmax and AUC of trilaciclib increase proportionally with dose.

    Route of Elimination

    79.1% of a radiolabelled dose is recovered in the feces, 7% as the unchanged parent compound. 14% of a radiolabelled dose is recovered in the urine, 2% as the unchanged parent compound.

    Volume of Distribution

    The volume of distribution of trilaciclib at steady state is 1130 L.

    Clearance

    The clearance of trilaciclib is 158 L/h.

    5.5 Metabolism/Metabolites

    Data regarding the metabolism of trilaciclib are not readily available, however it is expected to be extensively metabolised.

    5.6 Biological Half-Life

    The mean terminal half life of trilaciblib is approximately 14 h.

    5.7 Mechanism of Action

    Trilaciclib is inhibits cyclin-dependant kinase 4 (CDK4) at a concentration of 1 nmol/L and cyclin-dependent kinase 5 (CDK5) at 4 nmol/L. Inhibition of CDK2, CDK5, and CDK7 is over 1000-fold less at these concentrations and inhibition of CDK9 is 50-fold less. CDK4 and CDK5 are expressed in hematopoietic stem cells and progenitor cells. They are capable of phosphorylating and inactivating the retinoblastoma protien; a tumor suppressor. When trilaciclib is given to patients with retinoblastoma protein-null small cell lung cancer, it does not interfere with the intended chemotherapy induced cytotoxicity of cancer cells. Inhibition of CDK4 and CDK5 leads to a reversible pause in the cell cycle in the G1 phase for approximately 16 hours. The temporary cell cycle arrest prevents chemotherapy induced DNA damage in healthy cells, reducing the activity of caspases 3 and 7, which reduces apoptosis of healthy cells. Other studies have shown inhibitors of CDK4 and CDK6 enhance T-cell activation, upregulating major histocompatibility complex (MHC) class I and II, and stabilize programmed death-ligand 1 (PD-L1). Together these activities increase T-cell activity, increase antigen presentation, and sensitize cells to immune checkpoint inhibitors.