JNJ-42396302

Based on the information provided in the pdf file the compound looks potent, selective, and cell-permeable. I would recommend to use JNJ-42396302 as a chemical probe both in vitro and in cell-based assays. The compound shows high binding affinity (Ki = 13 nM) against PDE10A in vitro and great > 250-fold selectivity against other PDEs. The compound is also inactive or weak against a broad panel of enzymes at up to 10uM concentration. The data demonstrate the on-target activity of the compound in the HEK293 cells 1-10uM concentration range in a luciferase reporter assay. Suggesting that the compound is cell-permeable and active in cell-based assays. However, a direct target engagement (binding tp PDE10A) in cells is not shown. The rat studies demonstrate the tolerance to up to 40mg/kg of JNJ-42396302, and the determined ED50 0f 1.4 mg/kg demonstrates the potency of the compound in vivo.

Limited cell assay data is made available, with the increase in observed effects between 2.3 and 10 µM suggesting a cellular potency >5 µM (significant uncertainty in this estimate). In addition, cell data is only shown for overexpressed mouse enzyme in a HEK293 cell background and with a two orders of magnitude drop-off from the biochemical data. A mechanistic understanding of this drop-off is needed to understand probe fitness for cellular studies.