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BackgroundEpidermal growth factor receptor (EGFR) is an attractive therapeutic target for a number of human tumors including non-small cell lung cancer (NSCLC). Most patients with NSCLC and somatic mutations have shown a dramatic initial clinical response to reversible EGFR inhibitors. The clinical efficacy of reversible inhibitors is, however, ultimately limited due to the emergence of drug resistance, which is usually conferred by the EGFR T790M mutation. Importantly, irreversible, synthetic small molecule inhibitors are currently evaluated and some of them have been shown to overcome the acquired resistance that is oftentimes observed in these patients. Thus far, irreversible EGFR inhibitors as a drug class have not received regulatory approval due in part to their poor effectiveness at clinically achievable concentrations. Therefore, there is an urgent need to discover and develop novel, potent irreversible inhibitors against the EGFR T790M mutation.Material and methodsIn the following study, we report a novel “hybrid strategy” to identify irreversible EGFR inhibitors with active scaffolds starting with the identification and extraction of a common chemical reactive feature and a pharmacophore feature. The chemical reactive feature was elucidated by investigating 138 currently known irreversible inhibitors at B3LYP/6-31G(d) level using the density function theory method. The pharmacophore feature was extracted from the same inhibitors using pharmacophore modeling. Based on these unique features, two constraints were set while calibrating the protocols of in silico screening. Compounds bearing these specific features were obtained from the National Cancer Institute diversity database to form our subsequent library. Finally, a structure based virtual screening against the library was conducted using standard protocols validated in our lab.ResultsTwenty-eight candidate compounds that demonstrated antitumor activity and that had novel scaffolds different from commonly known quinazoline/quinoline analogs were obtained. The interaction modes between three representative candidates and our model system are similar to that between the model system and the reference compound T-001, which has previously been reported to be one of the most potent of the 138 irreversible inhibitors.ConclusionThe hybrid strategy starting with the extraction of common features is an effective approach to design potential irreversible inhibitors with novel scaffolds and therefore to obtain lead molecules in the selection process. These candidates possessing unique scaffolds have a strong likelihood to act as further starting points in the preclinical development of potent irreversible T790M EGFR inhibitors.

Fifty two compounds based on 5-nitropyrimidine-2,4-dione moiety have been synthesized and evaluated for their inhibitory potency on the production of nitric oxide. Among them, compound 36 inhibited the production of nitric oxide (IC50 : 8.6 μm) on lipopolysaccharide-induced RAW 264.7 cells and inducible nitric oxide synthase activity (IC50 : 6.2 μm), as well as exerted no potential cytotoxicity (IC50 > 80.0 μm). Docking study confirmed that compound 36 was an inducible nitric oxide synthase inhibitor with perfect binding to the active site of inducible nitric oxide synthase. At a dose of 10 mg/kg, oral administration of 36 possessed protective properties in carrageenan-induced paw edema of male ICR mice.

Iron metabolism dysregulation is tightly associated with cancer development. But the underlying mechanisms remain poorly understood. Increasing evidence has shown that long noncoding RNAs (lncRNAs) participate in various metabolic processes via integrating signaling pathway. In this study, we revealed one iron-triggered lncRNA, one target of YAP, LncRIM (LncRNA Related to Iron Metabolism, also named ZBED5-AS1 and Loc729013), which effectively links the Hippo pathway to iron metabolism and is largely independent on IRP2. Mechanically, LncRIM directly binds NF2 to inhibit NF2-LATS1 interaction, which causes YAP activation and increases intracellular iron level via DMT1 and TFR1. Additionally, LncRIM-NF2 axis mediates cellular iron metabolism dependent on the Hippo pathway. Clinically, high expression of LncRIM correlates with poor patient survival, suggesting its potential use as a biomarker and therapeutic target. Taken together, our study demonstrated a novel mechanism in which LncRIM-NF2 axis facilitates iron-mediated feedback loop to hyperactivate YAP and promote breast cancer development.