Enzastaurin (LY317615)

Catalog No.S1055

Enzastaurin (LY317615) Chemical Structure

Molecular Weight(MW): 515.61

Enzastaurin (LY317615) is a potent PKCβ selective inhibitor with IC50 of 6 nM in cell-free assays, 6- to 20-fold selectivity against PKCα, PKCγ and PKCε. Phase 3.

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Cited by 31 Publications

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Biological Activity

Description Enzastaurin (LY317615) is a potent PKCβ selective inhibitor with IC50 of 6 nM in cell-free assays, 6- to 20-fold selectivity against PKCα, PKCγ and PKCε. Phase 3.
Targets
PKCβ [1]
(Cell-free assay)		 PKCα [1]
(Cell-free assay)		 PKCγ [1]
(Cell-free assay)		 PKCε [1]
(Cell-free assay)
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. [1] 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. [2]
Assay
Methods Test Index PMID
Western blot
p27 / Cyclin D1 / Bcl-2 / Survivin ; 

PubMed: 22253748     


Cells were treated with enzastaurin for 72 hours and analyzed by immunoblot analysis. WT = GNAQ wild type; MT = GNAQ mutation.

p-ERK / ERK / p-AKT / AKT ; 

PubMed: 22253748     


Cells were treated with enzastaurin for 72 hours and analyzed for the expression of Akt and Erk1/2 and their phosphorylation by immunoblot analysis. WT = GNAQ wild type; MT = GNAQ mutation.

PKCα / PKCβ / PKCδ / PKCε / PKCθ / p-PKCε / p-PKCθ; 

PubMed: 22253748     


A and B, enzsaurin reduced the expression and phosphorylation of PKCβ, PKCε and PKCθ. Cells were treated with enzastaurin for 6 hours in the absence of serum (A) or for 72 hours in the presence of 10% FBS (B). pPKCε Thr566 was detected using pan p-PKC antibody raised against pPKCζ Thr410. Note that the expression of PKCβ was under detectable level of Western blot in Mel285 cells (B). 

p-eIF2a / eIF2a / p-ATF2 / ATF2 / CHOP / p21 / ATF6 / IRE1α ; 

PubMed: 19018094     


Protein profiling of MM cells exposed to enzastaurin. MM.1S cells were exposed to enzastaurin for increasing time periods followed by immunoblot analysis with the indicated antibodies. Tunicamycin (TM) was used as a positive control for ER stress signaling. 

22253748 19018094
Growth inhibition assay
Cell viability; 

PubMed: 22253748     


Enzastaurin exhibited greater antiproliferative effects on UM cell lines carrying GNAQ mutations (MT) than those with wild type GNAQ (WT). Cells were treated with varying amount of enzastaurin for 72 hours and subjected to MTS assay. Results are presented as mean ± SD of percent viability from three independent experiments.

22253748
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. [3]

Protocol

Kinase Assay:

[1]
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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.
Cell Research:

[1]
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  • 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.


    (Only for Reference)
Animal Research:[1] [3]
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  • Animal Models: Athymic nude mice; Mouse besring human MM tumors
  • Formulation: 10% acacia in water; dissolved in 100% ethanol and diluted 1:10 in D5W
  • Dosages: 75 mg/kg twice daily; 30 mg/kg twice daily
  • Administration: By gavage
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 30 mg/mL (58.18 mM)
Water Insoluble
Ethanol Insoluble
In vivo Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
15% Captisol
For best results, use promptly after mixing. 		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.

Chemical Information

Molecular Weight 515.61
Formula

C32H29N5O2
CAS No. 170364-57-5
Storage powder
in solvent
Synonyms N/A

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Clinical Trial Information

NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT03263026 Recruiting Drug: Enzastaurin Hydrochloride|Other: R-CHOP + placebo Diffuse Large B-Cell Lymphoma Denovo Biopharma LLC March 20 2018 Phase 3
NCT01432951 Completed Drug: Enzastaurin Solid Tumor|Lymphoma Malignant Eli Lilly and Company November 2011 Phase 1
NCT01388335 Completed Drug: warfarin|Drug: enzastaurin Solid Tumor|Lymphoma Malignant Eli Lilly and Company August 2011 Phase 1
NCT00744991 Completed Drug: Enzastaurin Cutaneous T-Cell Lymphoma Eli Lilly and Company September 2008 Phase 2
NCT00709995 Completed Drug: Enzastaurin|Drug: Sunitinib|Drug: Placebo Metastatic Renal Cell Carcinoma Eli Lilly and Company June 30 2008 Phase 2
NCT00530621 Completed Drug: enzastaurin|Drug: placebo|Drug: pemetrexed Non-small Cell Lung Cancer Eli Lilly and Company September 2007 Phase 2

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PKC Signaling Pathway Map

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID