Details
Stereochemistry | ACHIRAL |
Molecular Formula | C25H22N6O2 |
Molecular Weight | 438.4812 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
CN1CCN(CC1)C2=NC(C3=C(C(=O)NC3=O)C4=CNC5=C4C=CC=C5)=C6C=CC=CC6=N2
InChI
InChIKey=OAVGBZOFDPFGPJ-UHFFFAOYSA-N
InChI=1S/C25H22N6O2/c1-30-10-12-31(13-11-30)25-27-19-9-5-3-7-16(19)22(28-25)21-20(23(32)29-24(21)33)17-14-26-18-8-4-2-6-15(17)18/h2-9,14,26H,10-13H2,1H3,(H,29,32,33)
Sotrastaurin, an orally-active, first-in-class immunomodulator, is under development by Novartis for the treatment of uveal melanoma and diffuse-large B-cell lymphoma. Sotrastaurin is a low molecular mass synthetic compound
that potently inhibits the PKC α, β and the θ isoforms
resulting in selective NF-κB inactivation. Sotrastaurin is a potent and selective pan-PKC inhibitor, mostly for PKCθ with Ki of 0.22 nM in a cell-free assay. 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. PKC, a family of serine/threonine protein kinases overexpressed in certain types of cancer cells, is involved in cell differentiation, mitogenesis, inflammation, and the activation and survival of lymphocytes. Sotrastaurin is currently in phase II trials by Novartis for the treatment of large B-cell lymphoma and uveal melanoma. Sotrastaurin was in Phase II of clinical development for the prevention of acute rejection after solid organ transplantation and psoriasis, but this reseach had being discontinued.
Originator
Sources: http://adisinsight.springer.com/drugs/800019748
Curator's Comment: # Novartis; Ohio State University
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL3920 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19491325 |
0.22 nM [Ki] | ||
Target ID: CHEMBL299 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19491325 |
0.95 nM [Ki] | ||
Target ID: CHEMBL2996 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19491325 |
2.1 nM [Ki] | ||
Target ID: CHEMBL3616 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19491325 |
1.8 nM [Ki] | ||
Target ID: CHEMBL3045 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19491325 |
0.64 nM [Ki] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | Unknown Approved UseUnknown |
|||
Primary | Unknown Approved UseUnknown |
PubMed
Title | Date | PubMed |
---|---|---|
Gateways to clinical trials. | 2008 Apr |
|
Sotrastaurin and cyclosporine drug interaction study in healthy subjects. | 2010 Jul |
|
Docetaxel Facilitates Endothelial Dysfunction through Oxidative Stress via Modulation of Protein Kinase C Beta: The Protective Effects of Sotrastaurin. | 2015 May |
Patents
Sample Use Guides
In Vivo Use Guide
Sources: https://clinicaltrials.gov/ct2/show/NCT02273219
Uveal melanoma treatment: oral, 100-400 mg twice daily
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/19491325
Sotrastaurin (< 10uM) treatment effectively abrogated at low nanomolar concentration markers of early T-cell activation, such as interleukin-2 secretion and CD25 expression, in primary human and mouse T cells. Sotrastaurin (200 nM) inhibits the CD3/CD28 antibody- and alloantigen-induced T-cell proliferation responses in the absence of nonspecific antiproliferative effects. Sotrastaurin (<3 uM) markedly inhibits lymphocyte function-associated antigen-1-mediated T-cell adhesion.
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C2089
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ACTIVE MOIETY
SALT/SOLVATE (PARENT)