sotrastaurin (AEB071)

Compared to other PKC inhibitors, such as sotrastaurin and enzastaurin, darovasertib is significantly more potent in inhibiting conventional (α, β) and novel (δ, ϵ, η, θ) PKC proteins and has a better tolerability and safety profile. Current Phase I/II clinical trials indicated that darovasertib, combined with the Mitogen-activated protein kinase/Extracellular (MEK) inhibitors, binimetinib or crizotinib, produced a synergistic effect of uveal melanoma. In this article, we summarize the development of drugs for treating uveal melanomas and discuss problems associated with current treatments. We also discuss the mechanism of action, pharmacokinetic profile, adverse effects, and clinical trial for darovasertib, and future research directions for treating uveal melanoma.

Concurrent administration of sotrastaurin and binimetinib is feasible but associated with substantial gastrointestinal toxicity. Given the limited clinical activity achieved with this regimen, accrual to the phase II portion of the trial was not initiated.

Our study strongly suggests that SH3PXD2B is a carcinogenic molecule that can be used as a biomarker for GC detection, prognosis, treatment design, and follow-up.

In this study, we examined the signaling and functional effects of two PKC inhibitors (AEB071 and IDE196) in a panel of UM cell models. The differences in UM cell responses to PKC inhibition were not attributable to the degree or timing of PKC suppression or inhibition of the downstream mitogen-activated protein kinase (MAPK) or phosphatidylinositol-3-kinase (PI3K) pathways. Instead, UM cell show complex, PKC-independent signaling pathways that contribute to their survival and resistance to targeted therapies.

A combined targeting of PKC and a subtype specific driver molecule might complement specified breast cancer treatment.

Activity has been observed with the PKC inhibitors sotrastaurin (AEB071) and darovasertib (IDE196) in patients with UM. No objective responses were observed, and median progression-free survival was 8 weeks (range, 3-51 weeks). Although a tolerable dose of sotrastaurin and alpelisib was identified with pharmacodynamic evidence of target inhibition and without evidence of a corresponding immunosuppressive effect, limited clinical activity was observed.

We demonstrate that the PKC inhibitor sotrastaurin enhances the anti-leukemic activity of GSI in PDX models and completely abrogates the development of acquired GSI resistance in vitro. Overall, we highlight the potential of proteomics to dissect alterations in cellular signaling and identify druggable pathways in cancer.

Plasma from KPC-tumor bearing mice was used to treat C2C12 myotubes, with or without the PKC inhibitor Sotrastaurin...Prkcq null tumor-bearing mice also demonstrated increased survival versus wildtype controls (p<0.001). Our data suggest that chronic lipolysis associated with PDAC promotes myosteatosis and PKC-θ activation in muscle which promotes muscle dysfunction and wasting and further that inhibition of PKC-θ in muscle may be a beneficial treatment for PDAC cachexia.