In this issue, we present a collection of articles that tackle the challenges in the discovery and validation of new targets for clinical purposes, the application of chemical probes to understand the relationship between targets and biology and the expanding assortment of chemical tools and techniques that can be used to perturb targets that have been considered chemically intractable.




Stay on target p193


Applying a rigorous chemical biology approach to the selection and validation of clinical targets will increase the success of drug discovery initiatives.




Target validation using chemical probes pp195 - 199

Mark E Bunnage, Eugene L Piatnitski Chekler & Lyn H Jones


Fully profiled chemical probes are essential to support the unbiased interpretation of biological experiments necessary for rigorous preclinical target validation. We believe that by developing a 'chemical probe tool kit', and a framework for its use, chemical biology can have a more central role in identifying targets of potential relevance to disease, avoiding many of the biases that complicate target validation as practiced currently.


Determining target engagement in living systems pp200 - 205

Gabriel M Simon, Micah J Niphakis & Benjamin F Cravatt


Chemical probes are critical tools for elucidating the biological functions of proteins and can lead to new medicines for treating disease. The pharmacological validation of protein function requires verification that chemical probes engage their intended targets in vivo. Here we discuss technologies, both established and emergent, for measuring target engagement in living systems and propose that determining this parameter should become standard practice for chemical probe and drug discovery programs.


The why and how of phenotypic small-molecule screens pp206 - 209

Ulrike S Eggert


Small-molecule phenotypic screening has high potential in the discovery of new chemical probes and new biological small-molecule targets. This commentary will discuss the basic principles underlying the design of phenotypic screens and propose some guidelines to facilitate the discovery of small molecules from phenotypic screens.


Translational synthetic chemistry pp210 - 213

Sarathy Kesavan & Lisa A Marcaurelle


Providing chemical matter to modulate newly identified biological targets—as well as pre-existing but chemically intractable ones—remains a challenge in the discovery of therapeutics. Here, we discuss opportunities for synthetic chemists to make a direct impact in addressing targets that are considered 'undruggable'.


Review articles


Target identification and mechanism of action in chemical biology and drug discovery pp232 - 240

Monica Schenone, Vlado Dančík, Bridget K Wagner & Paul A Clemons