QNZ (EVP4593)

EVP4593 is an inhibitor of NF-κB pathway with IC50 value of 11nM [1].

EVP4593 is a quinazoline derivative. It is screened out from a luciferase reporter gene-based assay using human Jurkat T cells. EVP4593 is found as an inhibitor of PMA/PHA-induced NF-κB pathway. It shows significant inhibition of both NF-κB transcriptional activation and TNF-α production (IC50 value of 7nM). Additionally, EVP4593 also has anti-inflammatory efficacy. It inhibits edema formation in a rat carrageenin-induced paw edema model [1].

Since NF-κB pathway may play a direct role in Huntington’s disease (HD) pathogenesis, EVP4593 is found to have beneficial effects in Drosophila HD transgenic model. It significantly slows the progressive decline in the climbing speed without toxic effects [2].

References:
[1] Tobe M, Isobe Y, Tomizawa H, Nagasaki T, Takahashi H, Fukazawa T, Hayashi H. Discovery of quinazolines as a novel structural class of potent inhibitors of NF-kappa B activation. Bioorg Med Chem. 2003 Feb 6;11(3):383-91.
[2] Wu J, Shih HP, Vigont V, Hrdlicka L, Diggins L, Singh C, Mahoney M, Chesworth R, Shapiro G, Zimina O, Chen X, Wu Q, Glushankova L, Ahlijanian M, Koenig G, Mozhayeva GN, Kaznacheyeva E, Bezprozvanny. Neuronal store-operated calcium entry pathway as a novel therapeutic target for Huntington's disease treatment. Chem Biol. 2011 Jun 24;18(6):777-93.

Regorafenib induces extrinsic and intrinsic apoptosis through inhibition of ERK/NF-kappaB activation in hepatocellular carcinoma cells.[Pubmed:28000898]

Oncol Rep. 2017 Feb;37(2):1036-1044.

The aim of the present study was to investigate the role of NF-kappaB inactivation in regorafenib-induced apoptosis in human hepatocellular carcinoma SK-HEP-1 cells. SK-HEP-1 cells were treated with different concentrations of the NF-kappaB inhibitor 4-N-[2-(4-phenoxyphenyl)ethyl]quinazoline-4,6-diamine (QNZ) or regorafenib for different periods. The effects of QNZ and regorafenib on cell viability, expression of NF-kappaB-modulated anti-apoptotic proteins and apoptotic pathways were analyzed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, western blotting, DNA gel electrophoresis, flow cytometry and NF-kappaB reporter gene assay. Inhibitors of various kinases including AKT, c-Jun N-terminal kinase (JNK), P38 and extracellular signal-regulated kinase (ERK) were used to evaluate the mechanism of regorafenib-induced NF-kappaB inactivation. The results demonstrated that both QNZ and regorafenib significantly inhibited the expression of anti-apoptotic proteins and triggered extrinsic and intrinsic apoptosis. We also demonstrated that regorafenib inhibited NF-kappaB activation through ERK dephosphorylation. Taken all together, our findings indicate that regorafenib triggers extrinsic and intrinsic apoptosis through suppression of ERK/NF-kappaB activation in SK-HEP-1 cells.

The pentavalent antimonial therapy against experimental Leishmania amazonensis infection is more effective under the inhibition of the NF-kappaB pathway.[Pubmed:26218282]

Int Immunopharmacol. 2015 Sep;28(1):554-9.

During Leishmania infection, host immune response is important to prevent the growth/survival of intracellular amastigotes. In this study, we evaluated in vitro and in vivo whether or not during Leishmania amazonensis infection, pentavalent antimonial treatment/therapy could be more effective under TNF-alpha inhibition. Both L. amazonensis-infected macrophages (in vitro model) and mice (in vivo model) were treated with a nuclear factor-kappaB (NF-kappaB) inhibitor and with Glucantime(R), alone and in combined administrations. The in vitro amastigote counts, cytokines and nitrites' production were assessed after 48h incubation with the drugs. Paw lesion sizes and amastigote counts were also evaluated in vivo. Quantification of IL-1beta from the infected tissue was performed. In vitro results show that when infected macrophages were incubated with QNZ+Glucantime(R), a greater clearance was observed for the amastigotes' growth and this was related to greater nitrite production compared to the group that was only infected. In vivo results show that mice that received the combined treatment had their paw lesion sizes and amastigote nests inside the macrophages greatly diminished, correlating with increased IL-1beta levels.

QNZ (EVP4593) shows strong inhibitory effects on NF-κB transcriptional activation and TNF-α production with IC50s of 11 and 7 nM, respectively. QNZ (EVP4593) is a neuroprotective inhibitor of SOC channel.

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