Magic™ Anti-PhosphoY (Phospho Y) polyclonal antibody

Several lines of evidence suggest that the aggregation and deposition of amyloid-beta peptide (A beta) initiate the pathology of Alzheimer's disease (AD). Recently, a genome-wide association study demonstrated that a single-nucleotide polymorphism proximal to the EPHA4 gene, which encodes a receptor tyrosine kinase, is associated with AD risk. However, the molecular mechanism of EphA4 in the pathogenesis of AD, particularly in A beta production, remains unknown. Here, we performed several pharmacological and biological experiments both in vitro and in vivo and demonstrated that EphA4 is responsible for the regulation of A beta production. Pharmacological inhibition of EphA4 signaling and knockdown of Epha4 led to increased A beta levels accompanied by increased expression of beta-site APP cleaving enzyme 1 (BACE1), which is an enzyme responsible for A beta production. Moreover, EPHA4 overexpression and activation of EphA4 signaling via ephrin ligands decreased A beta levels. In particular, the sterile-alpha motif domain of EphA4 was necessary for the regulation of A beta production. Finally, EPHA4 mRNA levels were significantly reduced in the brains of AD patients, and negatively correlated with BACE1 mRNA levels. Our results indicate a novel mechanism of A beta regulation by EphA4, which is involved in AD pathogenesis.

Bruton's tyrosine kinase (BTK) is an attractive target for treating patients with B cell malignancies and autoimmune diseases. Many BTK inhibitors have been identified; however, like other kinase inhibitors, they lack diversity in their core structures. Therefore, it is important to secure a novel scaffold that occupies the adenine-binding site of BTK. We screened an in-house library of natural products and their analogs via a biochemical assay to identify a novel scaffold for targeting BTK. A pyranochromenone scaffold, derived from a natural active component decursin, was found to be effective at targeting BTK and was selected for further optimization. A series of pyranochromenone analogs was synthesized through the modification of pyranochromenone at the C7 position. Pyranochromenone compounds with an electrophilic warhead exhibited promising BTK inhibitory activity, with IC50 values in the range of 0.5-0.9 mu M. A docking study of the representative compound 8 provided a reasonable explanation for compound activity. Compound 8 demonstrated good selectivity over other associated kinases and decreased the production of proinflammatory cytokines in THP cells. Moreover, compound 8 presented significant in vivo efficacy in a murine model of collagen-induced arthritis.