Small-scale panel comprising diverse gene family targets to evaluate compound promiscuity

<p>Despite the recent advances in the life sciences and the remarkable investment in drug discovery research, the success rate of small-molecule drug development remains low. Safety is the second most influential factor of drug attrition in clinical studies; thus, the selection of compounds with fewer toxicity concerns is crucial to increase the success rate of drug discovery. Compounds that promiscuously bind to multiple targets are likely to cause unexpected pharmacological activity that may lead to adverse effects. Therefore, avoiding such compounds during early research stages would contribute to identifying the compounds with a higher chance of success in the clinic. To evaluate the interaction profile against a wide variety of targets, we constructed a small-scale promiscuity panel (PP) consisting of eight targets (ROCK1, PDE4D2, GR, PPARγ, 5-HT_2B, Adenosine A₃, M1 and GABA_A) that were selected from diverse gene families. The validity of this panel was confirmed by comparison with the promiscuity index evaluated from larger-scale panels. The promiscuity assessed using our PP correlated with the occurrence of both in vitro cytotoxicity and in vivo toxicity, suggesting that the small-scale PP is useful to identify compounds with fewer toxicity concerns and would lead to the reduction in drug attrition due to safety issues. In this annual meeting, we also introduce an in silico (QSAR) model which is constructed using the PP data. (Reprinted with permission from Chemical Research in Toxicology. Copyright 2019, American Chemical Society)</p>