1. Epigenetics
    TGF-beta/Smad
  2. PKC

Sotrastaurin (Synonyms: AEB071)

Cat. No.: HY-10343 Purity: 99.70%
Data Sheet SDS Handling Instructions

Sotrastaurin is a potent pan-PKC inhibitor, with Kis of 0.22 nM, 0.64nM, 0.95 nM, 1.8 nM, 2.1 nM and 3.2 nM for PKCθ, PKCβ, PKCα, PKCη, PKCδ and PKCε, respectively.

For research use only. We do not sell to patients.
Sotrastaurin Chemical Structure

Sotrastaurin Chemical Structure

CAS No. : 425637-18-9

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10 mM * 1 mL in DMSO $149 In-stock
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10 mg $220 In-stock
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Top Publications Citing Use of Products

    Sotrastaurin purchased from MCE. Usage Cited in: Cancer Res. 2015 Nov 1;75(21):4538-47.

    AEB071 downregulates APOBEC3B in multiple cancer cell lines. The histogram reports APOBEC3B mRNA levels normalized to the vehicle treated control for each line. The dotted line represents a 50% decrease of APOBEC3B expression due to AEB071. The corresponding immunoblots show APOBEC3B and TUBULIN levels. Each line is treated with AEB071 (10 μM) or vehicle control for 48 hours prior to mRNA and protein analysis.
    • Biological Activity

    • Protocol

    • Technical Information

    • Purity & Documentation

    • References

    Description

    Sotrastaurin is a potent pan-PKC inhibitor, with Kis of 0.22 nM, 0.64nM, 0.95 nM, 1.8 nM, 2.1 nM and 3.2 nM for PKCθ, PKCβ, PKCα, PKCη, PKCδ and PKCε, respectively.

    IC50 & Target

    IC50: 0.22 nM (PKCθ), 0.64 nM (PKCβ), 0.95 nM (PKCα), 1.8 nM (PKCη), 2.1 nM (PKCδ), 3.2 nM (PKCε)[1]

    In Vitro

    In cell-free kinase assays Sotrastaurin (AEB071) inhibits PKC, with Ki values in the subnanomolar to low nanomolar range. When Sotrastaurin is tested on a selected panel of kinases, the only enzyme on which Sotrastaurin displays an IC50value below 1 μM is glycogen synthase kinase 3β[1]. Sotrastaurin (AEB071) inhibits p-MARCKS, a PKC substrate, and pS6 in all the cell lines, independently of the mutational status. There is a slight inhibition of pERK at lower doses also in the GNA11 mutant cells, but not in the WT cells at any concentrations. This is consistent with previous reports indicating that Sotrastaurin inhibits ERK1/2 phosphorylation in GNAQ mutant cell lines[2].

    In Vivo

    The combination therapy results in a significantly enhanced reduction in tumor volume when compared to either Sotrastaurin (AEB071) or BYL719 alone (p=0.049 vs. BYL719 and p=0.022 vs. Sotrastaurin at day 26). There is even a greater effect when compared to vehicle control (p=0.016)[2]. Sotrastaurin (STN) treatment of liver donors and orthotopic liver transplantation (OLT) recipients (Gr.I) or of OLT recipients alone (Gr.II) prolongs animal survival, as 9 out of 10 rats in Gr. I, and 6 out of 6 rats in Gr.II survive >14 days. In contrast, only 4 out of 10 control OLT recipients remain alive at day 14 (p<0.01)[3].

    Clinical Trial
    NCT Number Sponsor Condition Start Date Phase
    NCT00545259 Novartis de Novo Liver Transplantation October 2007 Phase 1
    NCT00504543 Novartis Pharmaceuticals|Novartis Kidney Transplantation July 2007 Phase 2
    NCT02273219 Richard D. Carvajal|Columbia University Uveal Melanoma November 2014 Phase 1
    NCT00409929 Novartis Healthy June 2006 Phase 1
    NCT01854606 Novartis Pharmaceuticals|Novartis CD79 Mutant or ABC-subtype Diffuse Large B-Cell Lymphoma December 5, 2013 Phase 1
    NCT01430416 Novartis Pharmaceuticals|Novartis Uveal Melanoma December 20, 2011 Phase 1
    NCT01801358 Array BioPharma Uveal Melanoma August 2013 Phase 1|Phase 2
    NCT01402440 Novartis Pharmaceuticals|Novartis Diffuse Large B-Cell Lymphoma November 2011 Phase 1
    NCT00416546 Novartis Healthy October 2006 Phase 1
    NCT00615693 Novartis Uveitis|Posterior Uveitis|Panuveitis July 2008 Phase 2
    NCT00820911 Novartis Pharmaceuticals|Novartis Kidney Transplantation September 2008 Phase 2
    NCT00885196 Novartis Pharmaceuticals|Novartis Moderate and Severe Plaque Psoriasis April 2009 Phase 2
    NCT00572585 Novartis Pharmaceuticals|Novartis Ulcerative Colitis April 2010 Phase 2
    NCT00403416 Novartis Pharmaceuticals|Novartis Kidney Transplantation October 2006 Phase 1|Phase 2
    NCT00492869 Novartis Pharmaceuticals|Novartis Kidney Transplantation January 2007 Phase 1|Phase 2
    NCT00555789 Novartis Pharmaceuticals|Novartis Kidney Transplantation October 2007 Phase 2
    NCT00545259 Novartis de Novo Liver Transplantation October 2007 Phase 1
    NCT00504543 Novartis Pharmaceuticals|Novartis Kidney Transplantation July 2007 Phase 2
    NCT02273219 Richard D. Carvajal|Columbia University Uveal Melanoma November 2014 Phase 1
    NCT00409929 Novartis Healthy June 2006 Phase 1
    NCT01854606 Novartis Pharmaceuticals|Novartis CD79 Mutant or ABC-subtype Diffuse Large B-Cell Lymphoma December 5, 2013 Phase 1
    NCT01430416 Novartis Pharmaceuticals|Novartis Uveal Melanoma December 20, 2011 Phase 1
    NCT01801358 Array BioPharma Uveal Melanoma August 2013 Phase 1|Phase 2
    NCT01402440 Novartis Pharmaceuticals|Novartis Diffuse Large B-Cell Lymphoma November 2011 Phase 1
    NCT00416546 Novartis Healthy October 2006 Phase 1
    NCT00615693 Novartis Uveitis|Posterior Uveitis|Panuveitis July 2008 Phase 2
    NCT00820911 Novartis Pharmaceuticals|Novartis Kidney Transplantation September 2008 Phase 2
    NCT00885196 Novartis Pharmaceuticals|Novartis Moderate and Severe Plaque Psoriasis April 2009 Phase 2
    NCT00572585 Novartis Pharmaceuticals|Novartis Ulcerative Colitis April 2010 Phase 2
    NCT00403416 Novartis Pharmaceuticals|Novartis Kidney Transplantation October 2006 Phase 1|Phase 2
    NCT00492869 Novartis Pharmaceuticals|Novartis Kidney Transplantation January 2007 Phase 1|Phase 2
    NCT00555789 Novartis Pharmaceuticals|Novartis Kidney Transplantation October 2007 Phase 2
    NCT02285244 James Blachly|Novartis|Ohio State University Comprehensive Cancer Center Prolymphocytic Leukemia|Recurrent Mantle Cell Lymphoma|Recurrent Small Lymphocytic Lymphoma|Refractory Chronic Lymphocytic Leukemia|Richter Syndrome March 12, 2015 Phase 2
    NCT01064791 Novartis Pharmaceuticals|Novartis Renal Transplantation December 2009 Phase 2
    NCT01128335 Novartis Pharmaceuticals|Novartis Liver Transplantation April 2010 Phase 2
    NCT01594255 Novartis Pharmaceuticals|Novartis Healthy July 2009 Phase 1
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    References
    Preparing Stock Solutions
    Concentration Volume (DMSO) Mass 1 mg 5 mg 10 mg
    1 mM 2.2806 mL 11.4030 mL 22.8061 mL
    5 mM 0.4561 mL 2.2806 mL 4.5612 mL
    10 mM 0.2281 mL 1.1403 mL 2.2806 mL
    Kinase Assay
    [1]

    Classical and novel PKC isotypes are assayed by scintillation proximity assay technology. In brief, the assay is performed in 20 mM Tris-HCl buffer, pH 7.4, and 0.1% bovine serum albumin by incubating 1.5 μM of the peptide substrate with 10 μM [33P]ATP, 10 mM Mg (NO3)2, 0.2 mM CaCl2, and PKC at a protein concentration varying from 25 to 400 ng/mL, and lipid vesicles containing 30 mol% phosphatidylserine, 5 mol% diacylglycerol (DAG), and 65 mol% phosphatidylcholine at a final lipid concentration of 0.5 μM. Incubation is performed for 60 min at room temperature. The reaction is stopped by adding 50 μL of a mixture containing 100 mM EDTA, 200 μM ATP, 0.1% Triton X-100, and 0.375 μg/well streptavidin-coated scintillation proximity assay beads in PBS without Ca2+ and Mg2+. Incorporated radioactivity is measured in a MicroBetaTrilux counter for 1 min. PKCζ is assayed. In situ Thr-219 autophosphorylation status analysis of PKCθ is done by a phospho-site-specific antibody[1]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    Cell Assay
    [2]

    Sotrastaurin (AEB071) is dissolved in DMSO (10 mM) and stored (−20°C), and then diluted with appropriate media before use[2].

    Cells are plated in a 96-well plate and treated with Sotrastaurin, BYL719 or DMSO at indicated concentrations for a period of 5 days. Viability is assessed using Cell Counting Kit. The Combination Index values are calculated using the CompuSyn software. Briefly explained, the plots generated by the CompuSyn software demonstrate the Y-axis combination index values, where CI<1, =1, and >1 indicate synergism, additive effect, and antagonism, respectively. The X-Axis represents the fractional activity, which reflects the fraction of cells inhibited by the treatments relative to vehicle control. For combination index studies, the concentrations tested included Sotrastaurin (0, 125, 250, 500, 1000 nM) and BYL719 (0, 250, 500, 1000, 2000 nM)[2]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    Animal Administration
    [2][3]

    Sotrastaurin (AEB071) is dissolved in DMSO and then diluted with PBS or saline (Mice)[2][3].

    Mice[2]
    6-8 week nu/nu SCID female mice bearing subcutaneously injected 92.1 tumors (7 mice/group) of 100mm3 diameter are treated with vehicle, Sotrastaurin (80mg/kg/d) TID and or BYL719 orally (50mg/kg/d) QD as single agents and in combination, 5 days/week for 2 weeks. After 2 weeks, two animals from each group are sacrificed and tumors are collected to analyze for Western blot. For Omm1 xenogratfs, 6-8 weeks athymic female mice bearing subcutaneously injected Omm1 tumors (7 mice/group) of 100 mm3 diameter are treated with vehicle, Sotrastaurin (80mg/kg/d) TID and or BYL719 orally (50mg/kg/d) QD as single agents and in combination, 5 days/week for 3 weeks. Tumors are homogenized with grinding resins kits. Tumors are collected to analyze for H&E, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Tumors are measured every 2 to 3 days with calipers, and tumor volumes are calculated. Toxicity is monitored by weight loss.
    Rat[3]
    Male Sprague-Dawley (SD) rats (230-250g) are used throughout.Livers from SD rats are stored at 4C in UW solution for 30h, and then transplanted to SD rats with revascularization. Sotrastaurin (30mg/kg b.i.d. via oral gavage) is used in two treatment protocols. In Gr. I (n=10), liver Sotrastaurin is given to liver donors (90min prior to organ harvest) and OLT recipients (90min prior to the transplant, and for three days post-OLT). In Gr. II (n=6), Sotrastaurin is administered to OLT recipients only (according to Gr. I protocol). Gr. III controls are treated with PBS (n=10). OLT survival is assessed at day 14. Separate cohorts in Gr. I (n=3-4/gr) are sacrificed at 6h and 24h; OLT and peripheral blood samples are collected for analyses. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    References
    M.Wt

    438.48

    Formula

    C₂₅H₂₂N₆O₂

    CAS No.

    425637-18-9

    Storage
    Powder -20°C 3 years
      4°C 2 years
    In solvent -80°C 6 months
      -20°C 1 month
    Shipping

    Room temperature in continental US; may vary elsewhere

    Solvent & Solubility

    10 mM in DMSO

    * "<1 mg/mL" means slightly soluble or insoluble. "≥" means soluble, but saturation unknown.

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