The accession numbers for sequencing data are SRP111763 and SRP111797.

Constitutive activation of signal transducer and activator of transcription 3 (STAT3) has been validated as an attractive therapeutic target for cancer therapy. To stop both STAT3 activation and dimerization, a viable strategy is to design inhibitors blocking its SH2 domain phosphotyrosine binding site that is responsible for both actions. A new fragment-based drug design (FBDD) strategy, in silico site-directed FBDD, was applied in this study. A designed novel compound, 5,8-dioxo-6-(pyridin-3-ylamino)-5,8-dihydronaphthalene-1-sulfonamide (LY5), was confirmed to bind to STAT3 SH2 by fluorescence polarization assay. In addition, four out of the five chosen compounds have IC50 values lower than 5 μM for the U2OS cancer cells. 8 (LY5) has an IC50 range in 0.5-1.4 μM in various cancer cell lines. 8 also suppresses tumor growth in an in vivo mouse model. This study has demonstrated the utility of this approach and could be used to other drug targets in general.

Cytosolic DNA activates cGAS (cytosolic DNA sensor cyclic AMP-GMP synthase)-STING (stimulator of interferon genes) signaling, which triggers interferon and inflammatory responses that help defend against microbial infection and cancer. However, aberrant cytosolic self-DNA in Aicardi–Goutière’s syndrome and constituently active gain-of-function mutations in STING in STING-associated vasculopathy with onset in infancy (SAVI) patients lead to excessive type I interferons and proinflammatory cytokines, which cause difficult-to-treat and sometimes fatal autoimmune disease. Here, in silico docking identified a potent STING antagonist SN-011 that binds with higher affinity to the cyclic dinucleotide (CDN)-binding pocket of STING than endogenous 2′3′-cGAMP. SN-011 locks STING in an open inactive conformation, which inhibits interferon and inflammatory cytokine induction activated by 2′3′-cGAMP, herpes simplex virus type 1 infection, Trex1 deficiency, overexpression of cGAS-STING, or SAVI STING mutants. In Trex1−/− mice, SN-011 was well tolerated, strongly inhibited hallmarks of inflammation and autoimmunity disease, and prevented death. Thus, a specific STING inhibitor that binds to the STING CDN-binding pocket is a promising lead compound for STING-driven disease.

ZnO tetrapods and ZnO nanorods were synthesized on ZnO nanocrystal substrates by a vapor transport process. The source materials were ZnCO3 powder and ZnO powder, respectively, which were reduced by graphite powder to yield different amounts of the vapor. The catalysts were ZnO nanocrystal layers prepared by successive ionic layer adsorption and reaction method. The effect of the source materials on the structure was investigated. Results showed that for the source of ZnCO3 powder, ZnO tetropds constituted by the four pillarlike ZnO nanorods were obtained, while for the source of ZnO powder a nanorods array was formed. Possible growth mechanism and room-temperature photoluminescence of ZnO nanostructures are discussed.

Background: Persistent STAT3 phosphorylation is detected in medulloblastoma and represents a viable target for therapeutic drug discovery. Results: LY5, a novel STAT3 inhibitor, suppressed STAT3 phosphorylation, nuclear translocation, target gene expression, cell migration, angiogenesis, and induced apoptosis in medulloblastoma cells. Conclusion: LY5 exhibited potent activity against STAT3 signaling in medulloblastoma cells. Significance: LY5 is a promising drug candidate for medulloblastoma therapy.