生物活性

• 描述The protein kinase C (PKC) family of serine-threonine protein kinases has been implicated in the processes that control cell proliferation, motility, invasion, and apoptosis. Enzastaurin is an ATP-competitive, selective inhibitor of PKC with IC50 values of 6nM, 39nM, 83nM and 110nM for PKCβ, PKCα, PKCγ, and PKCε, respectively^[3]. In vitro, Enzastaurin can inhibit cell proliferation, including H460, LXF289, H1395, A427, A549, and H1299 cell lines with IC50 values ranging in 5 - 12 μM^[4]. Enzastaurin suppressed the proliferation of U87MG glioblastoma cells, PC-2 prostate carcinoma cells, and HCT116 colon carcinoma cells with concentrations ranging from 1 – 10 μM. K-562, MOLT-4, HOP-92, and PC-3 were the most sensitive cell lines to enzastaurin. However, Prostate cancer cell line DU-145; Breast cancer cell lines HS-578T, BT-549, and T-47D; Melanoma cell line MALme-3M; Lung cancer cell lines HOP-62, NCIH23, NCI-H322m, and NCI-460. Ovarian cancer cell lines OVCAR-5 and SK-OV-3; The renal cell lines 786-0, A498, ACHN, RXF393, and TK-10 were not affected by Enzastaurin. Enzastaurin induced HT116 and U87MG cell apoptosis in the low micromolar range in 1 – 4 μM. Enzastaurin at 1 μM inhibited the activity of PKCβ, PKCγ, PKCδ, PKCθ, PKCξ, and PKCε by about 90% or more but did not show significant inhibition of PKCμ and PKCι. At 1 μM, enzastaurin also suppressed the activity of p70S6, PKCζ, and PKCη by nearly 50%. Treatment of HCT116 and U87MG cells with 1 μM enzastaurin did not inhibit ERK activity^[3]. In vivo, oral administration with enzastaurin at 75 mg/kg twice daily for 21 days significantly suppressed the growth of both HCT116 colon carcinoma and U87MG glioblastoma xenografts in mice. In both cultured HCT116 cells and in xenograft tumor tissues from the same cell lines, enzastaurin treatment suppressed GSK3h-Ser9 phosphorylation, indicating that GSK3h-Ser9 phosphorylation may serve as a reliable marker for enzastaurin activity^[3]. The phase I clinical trials for enzastaurin have shown that oral administration at 525 mg/d yields -2 μM mean steady-state plasma exposure of enzastaurin and its analytes. Enzastaurin has successfully advanced to phase II clinical trials for the treatment of refractory glioblastoma and DLBCL^[3].
• 作用机制Enzastaurin selectively inhibits PKC activity by interacting competitively at its ATP-binding site^[5].