Pharmacophore identification of c-Myc inhibitor 10074-G5.

A structure-activity relationship (SAR) study of the c-Myc (Myc) inhibitor 10074-G5 (N-([1,1'-biphenyl]-2-yl)-7-nitrobenzo[c][1,2,5]oxadiazol-4-amine, 1) - which targets a hydrophobic domain of the Myc oncoprotein that is flanked by arginine residues - was executed in order to determine its pharmacophore. Whilst the 7-nitrobenzofurazan was found to be critical for inhibitory activity, the ortho-biphenyl could be replaced with a para-carboxyphenyl group to furnish the new inhibitor JY-3-094 (3q). Around five times as potent as the lead with an IC(50) of 33 µM for disruption of the Myc-Max heterodimer, JY-3-094 demonstrated excellent selectivity over Max-Max homodimers, with no apparent effect at 100 µM. Importantly, the carboxylic acid of JY-3-094 improves the physicochemical properties of the lead compound, which will facilitate the incorporation of additional hydrophobicity that might enhance Myc inhibitory activity further still.

Studies on blast traumatic brain injury using in-vitro model with shock tube.

One of the major limitations in studying the mechanisms of blast-induced traumatic brain injury (bTBI) or screening therapeutics for protection is the lack of suitable laboratory model systems that can closely mimic the complex blast exposure. Although animal models of bTBI that use shock tubes to mimic blast exposure are available, no high throughput shock tube-based in-vitro models have been reported. Here, we report an in-vitro bTBI model using a compressed air-driven shock tube and mouse neuroblastoma/rat glioblastoma hybrid cells (NG108-15) or SH-SY5Y human neuroblastoma cells in tissue culture plates. Our data showed significant neurobiological effects with decreased adenosine triphosphate levels, increased cellular injury, lactate dehydrogenase release, and reactive oxygen species formation after blast exposure.