Background/Aims: The Nrf2 signaling pathway plays a pivotal role in neutralizing excess reactive oxygen species formation and therefore enhancing the endogenous cellular protection mechanism. Thus, activating this pathway may provide therapeutic options against oxidative stress-related disorders. We have recently applied a computer-aided drug design approach to the design and synthesis of novel Nrf2 enhancers. The current study was aimed at investigating the potential beneficial impact of (E)-5-oxo-1-(4-((2,4,6-trihydroxybenzylidene)amino)phenyl)pyrrolidine-3-carboxylic acid (SK-119) in skin oxidative damage models. Methods: SK-119, tested initially in PC-12 cells, attenuated oxidative stress-induced cytotoxicity concomitantly with Nrf2 activation. The potential impact of this compound was evaluated in skin-based disease models both in vitro (HaCaT cells) and ex vivo (human skin organ culture). Results: The data clearly showed the marked anti-inflammatory and photoprotection properties of the compound; SK-119-treated cells or tissues displayed a reduction in cytokine secretion induced by lipopolysaccharides (LPS) in a manner comparable with dexamethasone. In addition, topical application of SK-119 was able to block UVB-induced oxidative stress and attenuated caspase-mediated apoptosis, DNA adduct formation, and the concomitant cellular damage. Conclusion: These results indicate that SK-119 is an Nrf2 activator that can be used as a prototype molecule for the development of novel treatments of dermatological disorders related to oxidative stress.
The design and synthesis of a novel nuclear factor erythroid 2‐related factor 2 (Nrf2) enhancer is reported. Using a structure‐based virtual screening approach, several commercially available compounds were identified as having high probability to interact with the Nrf2‐binding pocket in the Kelch‐like ECH‐associated protein 1 (Keap1). Keap1 is an adaptor protein that recruits Nrf2 to a cullin‐3‐dependent ubiquitin ligase complex. The identified compounds were tested against rat pheochromocytoma PC‐12 cells for their cytoprotective activity, and one compound (SKT359126) demonstrated an Nrf2‐mediated cell‐protective effect. Based on the structure of SKT359126, 23 novel derivatives were synthesized and evaluated. Of the screened derivatives, 1‐{4‐[(3,4‐dihydroxybenzylidene)amino]phenyl}‐5‐oxopyrrolidine‐3‐carboxylic acid demonstrated better activity than the parent molecules in activating the Nrf2 transduction pathway in a dose‐ and time‐dependent manner. This compound represents a promising starting point for the development of therapeutics for the treatment of oxidative‐stress‐related diseases.
Differentiation therapy has been recently revisited as a prospective approach in cancer therapy by targeting the aberrant growth, and repairing the differentiation and cell death programs of cancer cells. However, differentiation therapy of solid tumors is a challenging issue and progress in this field is limited. We performed High Throughput Screening (HTS) using a novel dual multiplex assay to discover compounds, which induce differentiation of human colon cancer cells. Here we show that the protein arginine methyl transferase (PRMT) type 1 inhibitor, MS023, is a potent inducer of colon cancer cell differentiation with a large therapeutic window. Differentiation changes in the highly aggressive human colon cancer cell line (HT-29) were proved by proteomic and genomic approaches. Growth of HT-29 xenograft in nude mice was significantly delayed upon MS023 treatment and immunohistochemistry of tumor indicated differentiation changes. These findings may lead to development of clinically effective anti-cancer drugs based on the mechanism of cancer cell differentiation.
High-throughput nanomole-scale synthesis allows for late-stage functionalization (LSF) of compounds in an efficient and economical manner. Here, we demonstrated that copper-catalyzed azide–alkyne cycloaddition could be used for the LSF of covalent kinase inhibitors at the nanoscale, enabling the synthesis of hundreds of compounds that did not require purification for biological assay screening, thus reducing experimental time drastically. We generated crude libraries of inhibitors for the kinase MKK7, derived from two different parental precursors, and analyzed them via the high-throughput In-Cell Western assay. Select inhibitors were resynthesized, validated via conventional biological and biochemical methods such as western blots and liquid chromatography–mass spectrometry (LC-MS) labeling, and successfully co-crystallized. Two of these compounds showed over 20-fold increased inhibitory activity compared to the parental compound. This study demonstrates that high-throughput LSF of covalent inhibitors at the nanomole-scale level can be an auspicious approach in improving the properties of lead chemical matter.
Invited for this month's cover is Prof. Arie Gruzman (Bar‐Ilan University) and collaborators who have developed an Nrf2 enhancer. This compound activated the Nrf2 transduction pathway and because of this the translation of dozens of antioxidant cytoprotective proteins in a dose‐ and time‐dependent manner and protected PC‐12 cells against oxidative stress. Considering the imbalance between production and elimination of oxidative species involved in the pathophysiology of many human diseases, this compound is a promising starting point for the development of novel therapeutics for the treatment of oxidative‐stress‐related diseases. Read the full text of the article at https://doi.org/10.1002/cplu.201700539.
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