Volume 9 Issue 4, April 2013

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.

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.

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.

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'.

Proteins can self-assemble into functional states, or they can end up as aberrant and sometimes toxic aggregates. Metastable intermediate states are often detected in these processes, and their structural characterization provides vital information about the balance between functional and pathological behavior in living systems.

Secreted Hedgehog (Hh) proteins are essential in development, and their aberrant activity contributes to certain cancers. Chemically targeting a lipid modification of Hh proteins results in loss of their cellular activity, revealing new strategies for cancer intervention and elucidation of the role of lipids in signal transduction.

A small molecule called optovin acts as a light-sensitive ligand for an ion channel involved in the detection of painful sensory stimuli. This unexpected finding emerged from a behavioral screen in zebrafish and provides a tool for the remote control of pain by light.

The structure of a bacterial methane oxidation complex reveals how protein-protein interactions can mediate coupling of proton, electron and substrate delivery to a metal active site.

Bacteria find creative solutions to occupy a variety of environmental niches. A peptide isolated from a gold-associated microbe provides a new example of this adaptation, binding gold and precipitating it to protect the organism from metal toxicity.

The VAS1 aminotransferase regulates the shade avoidance response in Arabidopsis thaliana by shunting metabolic flux away from auxin and ethylene, two growth regulatory plant hormones.

Hedgehog acyltransferase (Hhat) attaches a palmitate to Sonic hedgehog, but the importance of this enzyme has been difficult to discern. RU-SKI 43 is a potent and selective inhibitor of Hhat in vitro and in cells that will allow scientists to investigate the importance of Hhat for Shh signaling.

A conjugate generated by expressed protein ligation between an antibody targeting dendritic cells (DCs) and an immune-stimulating double-stranded DNA reveals that DCs can mediate both innate and adaptive immunity and represents its potential utility as a vaccine adjuvant.

Optovin is a small molecule that renders zebrafish embryos responsive to light through generation of singlet oxygen and activation of the TrpA1b channel, providing a new tool for optogenetics.

NMR structures of the homodimeric repressor protein CylR2 collected from 25 °C to –16 °C provide glimpses of the molecular changes that occur during cold denaturation, yielding insights into protein folding and oligomerization.

A new small-molecule inhibitor that selectively binds an internal cavity in HIF-2α allosterically disrupts HIF-2α–ARNT interaction in vitro and in cells. This compound should allow scientists to interrogate HIF-2α's activity in hypoxia and cancer cells.

One pathway for lysine biosynthesis uses a carrier protein, LysW, to protect the substrate. LysW is now shown to mediate entry of a second substrate into the same metabolic pathway, with structural and biochemical evidence identifying an amino acid motif that determines substrate specificity.

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.