Chemical Genetics–Based Target Identification in Drug Discovery

Abstract

Identification of novel, validated targets remains a top priority in modern drug discovery. Chemical genetics represents a powerful approach to the discovery of new targets. Unlike the traditional target-based screen that relies on a predefined, sometimes poorly validated target, a chemical genetics-based phenotypic screen probes the entire molecular signaling pathway in an efficient and unbiased manner for the most drug-sensitive node. The most significant obstacle associated with this approach is identification of the efficacy targets of small-molecule probes. The huge potential of chemical genetics cannot be realized without the establishment of reliable mechanisms for target identification. In this article, we describe each essential element of the chemical genetics process, discuss common challenges that the field is facing, and critically review various biochemical and genetics approaches recently developed for target deconvolution. We also attempt to summarize lessons that we have collectively learned and provide a practical perspective to facilitate the advancement of chemical genetics.

Chemical Genetics Uncovers Novel Inhibitors of Lignification, Including p-Iodobenzoic Acid Targeting CINNAMATE-4-HYDROXYLASE

“…Finally, compounds can be applied easily to essentially any plant model system or crop, whereas a genetic perturbation needs to be introduced in one genotype at a time (Tóth and van der Hoorn, 2010). Thanks to these characteristics, chemical biology has been successful for drug discovery (Cong et al, 2012), and it is becoming increasingly more popular to discover molecular mechanisms of physiological processes in plants (De Rybel et al, 2009Dejonghe and Russinova, 2014;Hicks and Raikhel, 2014).…”

Targeting Unselective Autophagy of Cellular Aggregates

“…Natural products are instrumental to discover and validate therapeutically relevant targets (i.e., taxol and microtubule polymerization in oncology [164]), indications (i.e., rapamycin itself and immunosuppression/organ transplant [165]), and even previously unimaginable therapeutic areas (i.e., penicillin and antibacterials [166]). Chemical biology [167] and phenotype-based screening [168] define similar, man-driven processes: i.e., a cellular assay that determines the influence of each member of a suitable/drug-like chemical collection on a complex phenotype, such as induction of autophagy. Once a positive/hit is found, it is used to identify its molecular target in the cell, and to elucidate the influence of such target on the appearance and development of the phenotype.…”

Assay Design for High‐Throughput Screening

“…One major disadvantage with cell-based assays is the black box aspect where the target or targets that produced the readout are unknown. Target identification becomes a significant challenge that requires extensive effort, despite recent advances in this area [36][37][38][39]. In addition, some cellular readouts may be indirect and too downstream from the biological event of interest to complicate interpretation of small-molecule actions in the context of many intersecting signaling pathways.…”