Tau pathology reduction with SM07883, a novel, potent, and selective oral DYRK1A inhibitor: A potential therapeutic for Alzheimer's disease.

Dual-specificity tyrosine phosphorylation-regulated kinase-1A (DYRK1A) is known to phosphorylate the microtubule-associated tau protein. Overexpression is correlated with tau hyperphosphorylation and neurofibrillary tangle (NFT) formation in Alzheimer's disease (AD). This study assessed the potential of SM07883, an oral DYRK1A inhibitor, to inhibit tau hyperphosphorylation, aggregation, NFT formation, and associated phenotypes in mouse models. Exploratory neuroinflammatory effects were also studied. SM07883 specificity was tested in a kinase panel screen and showed potent inhibition of DYRK1A (IC50  = 1.6 nM) and GSK-3ß (IC50  = 10.8 nM) kinase activity. Tau phosphorylation measured in cell-based assays showed a reduction in phosphorylation of multiple tau epitopes, especially the threonine 212 site (EC50  = 16 nM). SM07883 showed good oral bioavailability in multiple species and demonstrated a dose-dependent reduction of transient hypothermia-induced phosphorylated tau in the brains of wild-type mice compared to vehicle (47%, p < 0.001). Long-term efficacy assessed in aged JNPL3 mice overexpressing the P301L human tau mutation (3 mg/kg, QD, for 3 months) exhibited significant reductions in tau hyperphosphorylation, oligomeric and aggregated tau, and tau-positive inclusions compared to vehicle in brainstem and spinal cord samples. Reduced gliosis compared to vehicle was further confirmed by ELISA. SM07883 was well tolerated with improved general health, weight gain, and functional improvement in a wire-hang test compared to vehicle-treated mice (p = 0.048). SM07883, a potent, orally bioavailable, brain-penetrant DYRK1A inhibitor, significantly reduced effects of pathological tau overexpression and neuroinflammation, while functional endpoints were improved compared to vehicle in animal models. This small molecule has potential as a treatment for AD.

Identification of Taxol-producing endophytic fungi isolated from Salacia oblonga through genomic mining approach.

The most promising anti-tumor agent developed in the past three decades is Taxol. It is proven to be effective against many cancers. It is necessary to isolate pharmacologically potent endophytic microbial strains from medicinal plants with special reference to Taxol production. In the current study, endophytic fungi were isolated from the bark of the medicinal plant, Salacia oblonga. The isolated endophytes were identified morphologically, and further characterized by ITS-PCR using genomic DNA samples, later the products were sequenced for identification and phylogenetic linkage mapping. The samples were screened for the potential to produce Taxol or taxanes, employing PCR. The resulted data have been sequenced to confirm the presence of the two genes implicated in Taxol biosynthesis, 10-deacetylbaccatin III-10-O-acetyl transferase (DBAT) and C-13 phenylpropanoid side chain-CoA acyltransferase (BAPT). Seven samples showed the amplicons of DBAT gene and one showed the amplicons of BAPT gene. Sequencing of these products was carried out, of which one sample has revealed sequence homology to the original DBAT gene from Taxus. The present work confirms and substantiates the potential of genomic mining approach to discover novel Taxol-producing endophytic fungi.