Enzastaurin

A potent, selective, ATP-competitive PKCβ inhibitor with IC50 of 6 nM; weakly inhibits PKCα, PKCγ, and PKCε with IC50 of 39, 83, and 110 nM, respectively; induces apoptosis and suppresses the proliferation of tumor cells, suppresses the phosphorylation of GSK3β Ser9, ribosomal protein S6(S240/244) and AKT(Thr308); suppresses tumor growth through multiple mechanism in vivo; orally active.Blood Cancer Phase 3 Discontinued(In Vitro):Enzastaurin (LY317615) application results in a marked dose-dependent inhibition of growth in all MM cell lines investigated, including MM.1S, MM.1R, RPMI 8226 (RPMI), RPMI-Dox40 (Dox40), NCI-H929, KMS-11, OPM-2, and U266, with IC50 from 0.6-1.6 μM. Enzastaurin direct impacts human tumor cells, inducing apoptosis and suppressing proliferation in cultured tumor cells. Enzastaurin also suppresses the phosphorylation of GSK3βser9, ribosomal protein S6S240/244, and AKTThr308 while having no direct effect on VEGFR phosphorylation.Enzastaurin increases apoptosis in malignant lymphocytes of CTCL. When combined with GSK3 inhibitors, enzastaurin demonstrates an enhancement of cytotoxicity levels. Treatment with a combination of enzastaurin and the GSK3 inhibitor AR-A014418 leads to increased levels of β-catenin total protein and β-catenin-mediated transcription. Blocking of β-catenin-mediated transcription or small hairpin RNA (shRNA) knockdown of β-catenin induces the same cytotoxic effects as that of enzastaurin plus AR-A014418. Additionally, treatment with enzastaurin and AR-A014418 decreases the mRNA levels and surface expression of CD44.(In Vivo):Treatment of xenografts with Enzastaurin and radiation produces greater reductions in density of microvessels than either treatment alone. The decrease in microvessel density corresponds to delayed tumor growth.