U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ACHIRAL
Molecular Formula C25H22N6O2.C2H4O2
Molecular Weight 498.5331
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of SOTRASTAURIN ACETATE

SMILES

CC(O)=O.CN1CCN(CC1)C2=NC(C3=C(C(=O)NC3=O)C4=CNC5=C4C=CC=C5)=C6C=CC=CC6=N2

InChI

InChIKey=RVEUYBMXVVDLFO-UHFFFAOYSA-N
InChI=1S/C25H22N6O2.C2H4O2/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;1-2(3)4/h2-9,14,26H,10-13H2,1H3,(H,29,32,33);1H3,(H,3,4)

HIDE SMILES / InChI

Description

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.

CNS Activity

Originator

Approval Year

Targets

Primary TargetPharmacologyConditionPotency
0.22 nM [Ki]
0.95 nM [Ki]
2.1 nM [Ki]
1.8 nM [Ki]
0.64 nM [Ki]

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown
Primary
Unknown

PubMed

Patents

Sample Use Guides

In Vivo Use Guide
Uveal melanoma treatment: oral, 100-400 mg twice daily
Route of Administration: Oral
In Vitro Use Guide
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.