An Engineered Synthetic Receptor-Aptamer Pair for an Artificial Signal Transduction System.

Cell membrane receptors regulate cellular responses through sensing extracellular environmental signals and subsequently transducing them. Receptor engineering provides a means of directing cells to react to a designated external cue and exert programmed functions. However, rational design and precise modulation of receptor signaling activity remain challenging. Here, we report an aptamer-based signal transduction system and its applications in controlling and customizing the functions of engineered receptors. A previously reported membrane receptor-aptamer pair was used to design a synthetic receptor system that transduces cell signaling depending on exogenous aptamer input. To eliminate the cross-reactivity of the receptor with its native ligand, the extracellular domain of the receptor was engineered to ensure that the receptor was solely activated by the DNA aptamer. The present system features tunability in the signaling output level using aptamer ligands with different receptor dimerization propensities. In addition, the functional programmability of DNA aptamers enables the modular sensing of extracellular molecules without the need for genetic engineering of the receptor.

Hit-to-lead optimization and kinase selectivity of imidazo[1,2-a]quinoxalin-4-amine derived JNK1 inhibitors.

As the result of a rhJNK1 HTS, the imidazo[1,2-a]quinoxaline 1 was identified as a 1.6 µM rhJNK1 inhibitor. Optimization of this compound lead to AX13587 (rhJNK1 IC50=160 nM) which was co-crystallized with JNK1 to identify key molecular interactions. Kinase profiling against 125+ kinases revealed AX13587 was an inhibitor of JNK, MAST3, and MAST4 whereas its methylene homolog AX14373 (native JNK1 IC50=47 nM) was a highly specific JNK inhibitor.

6-Position optimization of tricyclic 4-quinolone-based inhibitors of glycogen synthase kinase-3ß: discovery of nitrile derivatives with picomolar potency.

We previously disclosed tricylic, 6-carboxylic acid-bearing 4-quinolones as GSK-3ß inhibitors. Herein we discuss the optimization of this series to yield a series of more potent 6-nitrile analogs with insignificant anti-microbial activity. Finally, kinase profiling indicated that members of this class were highly specific GSK-3 inhibitors.

Synthesis and structure-activity relationship of 4-quinolone-3-carboxylic acid based inhibitors of glycogen synthase kinase-3ß.

The synthesis, GSK-3ß inhibitory activity, and anti-microbial activity of bicyclic and tricyclic derivatives of the 5,7-diamino-6-fluoro-4-quinolone-3-carboxylic acid scaffold were studied. Kinase selectivity profiling indicated that members of this class were potent and highly selective GSK-3 inhibitors.