Sotrastaurin, also known as AEB-071, is an orally available pan-protein kinase C (PKC) inhibitor with potential immunosuppressive and antineoplastic activities. Sotrastaurin inhibits both T- and B-cell activations via PKC theta and beta isozymes, respectively. Both PKCs are important in the activation of nuclear factor-kappaB (NF-kB). Inhibition of PKC beta in B-cells results in prevention of NF-kB-mediated signaling and down regulation of NF-kB target genes. This may eventually lead to an induction of G1 cell cycle arrest and tumor cell apoptosis in susceptible tumor cells. This agent may act synergistically with other chemotherapeutic agents.
CAS Number: 425637-18-9
Molecular Weight: 438.48
Chemical Name: 3-(1H-indol-3-yl)-4-(2-(4-methylpiperazin-1-yl)quinazolin-4-yl)-1H-pyrrole-2,5-dione
Appearance: Solid Power.
Purity: ≥98% (or refer to the Certificate of Analysis)
Solubility: Soluble in DMSO, not in water
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis
Storage Condition: Dry, dark and -20 oC for 1 year or refer to the Certificate of Analysis.
Shelf Life: ≥12 months if stored properly.
Stock Solution Storage: 0 - 4 oC for 1 month or refer to the Certificate of Analysis.
Drug Formulation: To be determined.
HS Tariff Code: 382200
How to use
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. 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.
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). 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).
- Yamashita K, Todo S. Sotrastaurin, a new selective protein kinase C inhibitor, on the way. Transplantation. 2012 Jan 27;93(2):146-7. PubMed PMID: 22129763.
- Merani S, McCall M, Pawlick RL, Edgar RL, Davis J, Toso C, Emamaullee JA, Kin T, Shapiro AM. AEB071 (sotrastaurin) does not exhibit toxic effects on human islets in vitro, nor after transplantation into immunodeficient mice. Islets. 2011 Nov-Dec;3(6):338-43. Epub 2011 Nov 1. PubMed PMID: 21934354.
- Kamo N, Shen XD, Ke B, Busuttil RW, Kupiec-Weglinski JW. Sotrastaurin, a protein kinase C inhibitor, ameliorates ischemia and reperfusion injury in rat orthotopic liver transplantation. Am J Transplant. 2011 Nov;11(11):2499-507. doi: 10.1111/j.1600-6143.2011.03700.x. Epub 2011 Aug 30. PubMed PMID: 21883905.
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