Enzastaurin (LY317615)
Product Description
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Molecular Weight:
515.61 Enzastaurin (LY317615) is a potent PKCβ selective inhibitor with IC50 of 6 nM, 6- to 20-fold selectivity against PKCα, PKCγ and PKCε. Phase 3.
Biological Activity
Protocol(Only for Reference)
Kinase Assay: [1]
Cell Assay: [1]
Animal Study: [1]
Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2015-02-07)
Chemical Information
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Molecular Weight:
515.61 Enzastaurin (LY317615) is a potent PKCβ selective inhibitor with IC50 of 6 nM, 6- to 20-fold selectivity against PKCα, PKCγ and PKCε. Phase 3.
Biological Activity
| Description | Enzastaurin (LY317615) is a potent PKCβ selective inhibitor with IC50 of 6 nM, 6- to 20-fold selectivity against PKCα, PKCγ and PKCε. Phase 3. | |||||
|---|---|---|---|---|---|---|
| Targets | PKCβ [1] | PKCα [1] | PKCγ [1] | PKCε [1] | ||
| IC50 | 6 nM | 39 nM | 83 nM | 110 nM | ||
| In vitro | Enzastaurin application results in a marked dose-dependent inhibition of growth in all MM cell lines investigated, including MM.1S, MM.1R, RPMI 8226 (RPMI), RPMI-Dox40 (Dox40), NCI-H929, KMS-11, OPM-2, and U266, with IC50 from 0.6-1.6 μM. Enzastaurin direct impacts human tumor cells, inducing Apoptosis and suppressing proliferation in cultured tumor cells. Enzastaurin also suppresses the phosphorylation of GSK3βser9, ribosomal protein S6S240/244, and AKTThr308 while having no direct effect on VEGFR phosphorylation. Enzastaurin increases apoptosis in malignant lymphocytes of CTCL. When combined with GSK3 Inhibitors, enzastaurin demonstrated an enhancement of cytotoxicity levels. Treatment with a combination of enzastaurin and the GSK3 inhibitor AR-A014418 led to increased levels of β-catenin total protein and β-catenin-mediated transcription. Blocking of β-catenin-mediated transcription or small hairpin RNA (shRNA) knockdown of β-catenin induced the same cytotoxic effects as that of enzastaurin plus AR-A014418. Additionally, treatment with enzastaurin and AR-A014418 decreased the mRNA levels and surface expression of CD44. | |||||
| In vivo | Treatment of xenografts with Enzastaurin and radiation produced greater reductions in density of microvessels than either treatment alone. The decrease in microvessel density corresponded to delayed tumor growth. | |||||
| Features | | |||||
Protocol(Only for Reference)
Kinase Assay: [1]
| Kinase inhibition assays | The inhibition of PKCβII, PKCα, PKCε, or PKCγ activity by enzastaurin is determined using a filter plate assay format measuring 33P incorporation into myelin basic protein substrate. Reactions are done in 100 μL reaction volumes in 96-well polystyrene plates with final conditions as follows: 90 mM HEPES (pH 7.5), 0.001% Triton X-100, 4% DMSO, 5 mM MgCl2, 100 μM CaCl2, 0.1 mg/mL phosphatidylserine, 5 μg/mL diacetyl glyerol, 30 μM ATP, 0.005 μCi/μL 33ATP, 0.25 mg/mL myelin basic protein, serial dilutions of enzastaurin (1-2,000 nM), and recombinant human PKCβII, PKCα, PKCε, or PKCγ enzymes (390, 169, 719, or 128 pM, respectively). Reactions are started by addition of the enzyme and incubated at room temperature for 60 minutes. They are then quenched with 10% H3PO4, transferred to multiscreen anionic phosphocellulose 96-well filter plates, incubated for 30 to 90 minutes, filtered and washed with 4 volumes of 0.5% H3PO4 on a vacuum manifold. Scintillation cocktail is added and plates are read on a Microbeta scintillation counter. IC50 values are determined by fitting a three-variable logistic equation to the 10-point dose-response data using ActivityBase 4.0. |
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Cell Assay: [1]
| Cell lines | HCT116 and U87MG cells |
|---|---|
| Concentrations | 0.3-4 μM |
| Incubation Time | 72 hours |
| Method | Induction of apoptosis by enzastaurin is measured by nucleosomal fragmentation and terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) and staining in HCT116 and U87MG cell lines. Briefly, 5 × 103 cells are plated per well in 96-well plates (1% FBS-supplemented media conditions), incubated with or without Enzastaurin for 48 to 72 hours. The absorbance values are normalized to those from control-treated cells to derive a nucleosomal enrichment factor at all concentrations as per the manufacturer's protocol. The concentrations studied ranges from 0.1 to 10 μM. In situ TUNEL staining is assayed with the In situ Cell Death Detection, Fluorescein kit. Cells (7.5 ?104) are plated per well in 6-well plates and incubated 72 hours in 1% FBS-supplemented media ?Enzastaurin. Fluorescein-labeled DNA strand breaks are detected with the BD epics flow cytometer. Ten thousand, single-cell, FITC-staining events are collected for each test. |
Animal Study: [1]
| Animal Models | Athymic nude mice | ||
|---|---|---|---|
| Formulation | 10% acacia in water | ||
| Dosages | 75 mg/kg twice daily | ||
| Administration | By gavage | ||
| Solubility | 15% Captisol, 30 mg/mL | ||
| * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations. | |||
Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)
| Species | Baboon | Dog | Monkey | Rabbit | Guinea pig | Rat | Hamster | Mouse |
| Weight (kg) | 12 | 10 | 3 | 1.8 | 0.4 | 0.15 | 0.08 | 0.02 |
| Body Surface Area (m2) | 0.6 | 0.5 | 0.24 | 0.15 | 0.05 | 0.025 | 0.02 | 0.007 |
| Km factor | 20 | 20 | 12 | 12 | 8 | 6 | 5 | 3 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
| Rat dose (mg/kg) = mouse dose (22.4 mg/kg) × | mouse Km(3) | = 11.2 mg/kg |
| rat Km(6) |
Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2015-02-07)
| NCT Number | Recruitment | Conditions | Sponsor /Collaborators | Start Date | Phases |
|---|---|---|---|---|---|
| NCT01432951 | Active, not recruiting | Solid Tumor|Lymphoma, Malignant | Eli Lilly and Company | November 2011 | Phase 1 |
| NCT01432951 | Active, not recruiting | Solid Tumor|Lymphoma, Malignant | Eli Lilly and Company | November 2011 | Phase 1 |
| NCT01388335 | Completed | Solid Tumor|Lymphoma, Malignant | Eli Lilly and Company | August 2011 | Phase 1 |
| NCT01388335 | Completed | Solid Tumor|Lymphoma, Malignant | Eli Lilly and Company | August 2011 | Phase 1 |
| NCT00685633 | Withdrawn | Prostate Cancer | Eastern Cooperative Oncology Group|National Cancer Instit ...more Eastern Cooperative Oncology Group|National Cancer Institute (NCI) | December 2008 | Phase 2 |
Chemical Information
| Molecular Weight (MW) | 515.61 |
|---|---|
| Formula | C32H29N5O2 |
| CAS No. | 170364-57-5 |
| Storage | 3 years -20℃Powder |
|---|---|
| 6 months-80℃in solvent (DMSO, water, etc.) | |
| Synonyms | |
| Solubility (25°C) * | In vitro | DMSO | 30 mg/mL (58.18 mM) |
|---|---|---|---|
| Water | <1 mg/mL ( | ||
| Ethanol | <1 mg/mL ( | ||
| In vivo | 15% Captisol | 30 mg/mL | |
| * <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations. | |||
| Chemical Name | 3-(1-methyl-1H-indol-3-yl)-4-(1-(1-(pyridin-2-ylmethyl)piperidin-4-yl)-1H-indol-3-yl)-1H-pyrrole-2,5-dione |
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| Stock Solution (1ml DMSO) | 1mM | 10mM | 20mM | 30mM |
|---|---|---|---|---|
| Mass(mg) | 0.51561 | 5.1561 | 10.3122 | 15.4683 |
Rating
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Source Arthritis Rheum 2013 65, 1022-31. Enzastaurin (LY317615) purchased from Selleck Method In vivo treatment Cell Lines Two-month-old female Sle1.Sle3 mice Concentrations 1.5 mg in 200 μl 10% acacia in water/per mouse Incubation Time 4 times weekly, orally, 8 weeks Results Treatment of Sle mice with the PKC-specific inhibitor enzastaurin prevented the development of lupus. Rating
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