1. Epigenetics
    TGF-beta/Smad
  2. PKC

Sotrastaurin (Synonyms: AEB071; AEB 071; AEB-071)

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

Sotrastaurin is a potent and selective pan-PKC inhibitor, with Ki 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

Size Price Stock Quantity
Free sample   Apply now  
10 mM * 1 mL in DMSO $149 In-stock
5 mg $135 In-stock
10 mg $220 In-stock
50 mg $855 In-stock
100 mg   Get quote  
200 mg   Get quote  

* Please select Quantity before adding items.

Top Publications Citing Use of Products
  • Biological Activity

  • Protocol

  • Technical Information

  • Purity & Documentation

  • References

Description

Sotrastaurin is a potent and selective pan-PKC inhibitor, with Ki 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
Sponsor Condition Start Date Phase
Novartis AG Liver transplant rejection 2010-04-30 Phase 2
Novartis AG Kidney transplantation 2009-12-31 Phase 2
Novartis AG Psoriasis 2009-04-30 Phase 2
Novartis AG Kidney transplantation 2007-07-31 Phase 2
Novartis AG Kidney transplant rejection 2008-09-30 Phase 2
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].

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].

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.

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

Purity: 99.70%

Inquiry Online

Your information is safe with us. * Required Fields.

Product name

 

Salutation

Applicant name *

 

Email address *

Phone number

 

Organization name *

Country *

 

Requested quantity *

Remarks

Bulk Inquiry

Inquiry Information

Product Name:
Sotrastaurin
Cat. No.:
HY-10343
Quantity: