Radiotherapy was widely applied for breast cancer treatment in clinical, while how to improve the radiation sensitivity of tumor and protect normal tissues form radiation damage had drawn considerable attention....
Background Proteasome inhibition demonstrates highly effective impact on multiple myeloma (MM) treatment. Here, we aimed to examine anti-tumor efficiency and underlying mechanisms of a novel well tolerated orally applicable proteasome inhibitor NNU546 and its hydrolyzed pharmacologically active form NNU219. Methods Enzyme activities and inhibition assays was performed to evaluate the effect of NNU219 on proteasome. To explore the anti-MM activity of NNU219 and its related mechanism, multiple in vitro assays such as cell viability, cell cycle and apoptosis assays, Co-immunoprecipitation (Co-IP) and ubiquitination, NF-κB inhibition assay were conducted. Furthermore, in vivo studies were performed to determine the effects of NNU219 on tumors. Results NNU219 showed more selective inhibition to proteasome catalytic subunits and less off-target effect than bortezomib ex vivo. Moreover, intravenous and oral administration of either NNU219 or NNU546 led to more sustained pharmacodynamic inhibitions of proteasome activities compared with bortezomib. Importantly, NNU219 exhibited potential anti-MM activity in both MM cell lines and primary samples in vitro. The anti-MM activity of NNU219 was associated with induction of G2/M-phase arrest, as well as induction of apoptosis via activation of the caspase cascade and endoplasmic reticulum stress response. At well-tolerated doses, significant growth-inhibitory effects of NNU219 and NNU546 were observed in 3 different human MM xenograft mouse models. Furthermore, such observation was even found in the presence of a bone marrow microenvironment. Conclusion Taken together, these findings provided the basis for clinical trial of NNU546 to determine its potential as a candidate for MM treatment.
The RNA‐dependent RNA polymerase (RdRp) of influenza virus, consisting of subunits of PA, PB1, and PB2 proteins, is responsible for viral mRNA transcription and vRNA replication. Cap‐dependent endonuclease (CEN) exists in PA subunit of RdRp and mediates the critical “cap‐snatching” step of viral RNA transcription, which is considered as a promising anti‐influenza target. In this manuscript, a series of novel compounds were designed, synthesized, and biologically investigated as CEN inhibitors. The cellular activities of the target compounds against influenza A/H1N1 virus were investigated and the structure–activity relationship (SAR) was summarized. The results showed that some compounds were active against influenza A/H1N1 virus with IC50 values of less than 100 μM. The microsomal metabolic stabilities were carried out in human, monkey, and rat species, and the results showed that the active ingredients of compounds 32 and 40 were stable enough to be in vivo investigated. The in vivo pharmacokinetic results showed that compound 32 had acceptable biological parameters for both ig and iv administrations. Then the in vivo toxicity study of compound 32 with the doses of 100 and 50 mg/kg BID was performed in BALB/C mice. No obvious toxicity of compound 32 was observed during the experiment. Finally, the in vivo efficacy study of compound 32 in BALB/C mice showed that it was effective in alleviating influenza symptoms and showed a significant pharmacodynamic dose dependence. These results indicated that compound 32 was a promising candidate for further development.
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