Volume 6 Issue 3, March 2010

Chemical biologists frequently aim to create small-molecule probes that interact with a specific protein in vitro in order to explore the role of the protein in a broader biological context (cells or organisms), but a common understanding of what makes a high-quality probe is lacking. Here I propose a set of principles to guide probe qualification.

Bioactive compounds are most frequently identified via high-throughput screening campaigns. This article discusses the strengths and weaknesses of the most popular screening approaches and the utility of compounds derived from them.

The complexity of cancer signaling and the resulting difficulties in target selection have strongly biased kinase drug discovery towards clinically validated targets. Recently, novel kinase targets that are uncharacterized have emerged from genome sequencing and RNAi studies. Chemical probes are urgently needed to functionally annotate these kinases and to stimulate new drug discovery efforts.

A high-throughput phenotypic screen in zebrafish embryos provides distinctive signatures by which neuroactive chemicals can be classified. These “behavioral barcodes” provide a systems approach to elucidating the mechanistic neuropharmacology of drugs and novel compounds.

Organic synthesis plays a leading role in the discovery of small molecules for the exploration of biological systems. Therefore, the development of efficient strategies for the preparation of these molecules is a necessary aspect of the small-molecule approach to chemical biology.

A reverse genetic engineering approach identifies metabolic enzymes and their cellular pathways as potential regulators of myoblast differentiation. Targeting these metabolic nodes has provocative implications for drug discovery and therapeutic efficacy.

Pd-catalyzed domino reactions have been shown to stitch together chemical groups to form more complex scaffolds. Now these methods are used in a diversity-oriented synthesis approach to make intricate natural product–like structures using simple sugars as starting materials.

Differentiation of mouse myoblasts is coordinated with glycolysis, calcium/calcineurin signaling, chromatin acetylation and cholesterol biosynthesis. This is consistent with profiling of the intracellular metabolites that accompany myogenic differentiation and points to new targets for cancer differentiation therapy of rhabdomyosarcoma.

Reversible cobalt complexation of alkynes is a critical step in some chemical transformations. New research shows this reaction can be used to specifically retrieve modified lipids from complex cellular mixtures, simplifying tracking and providing insights into lipid metabolism.

Cycloheximide is a natural product that cell biologists have used for decades as a tool to arrest protein synthesis in eukaryotes. Biochemical data now refine our mechanistic view of how cycloheximide and structurally related analogs inhibit translational elongation.

Group II introns can act as mobile genomic elements and integrate into genomic DNA through reverse splicing. A selective nucleotide modification approach was used to show that the 2′-hydroxyl at the ribozyme 3′ terminus plays a catalytic role as a proton shuttle during reverse splicing.

The prion strain phenomenon states that distinct amyloid conformations with different phenotypes and heritable states can arise from a single polypeptide. The decision about amyloid conformation is made at the level of the initial nucleus, where different nuclei will lead to different conformations.

Despite the need for new psychoactive drugs, there are few robust approaches for discovering novel neuroactive molecules. Development of a behavior-based high-throughput screen in zebrafish led to the discovery of molecules with neurological effects. Translating the complex behavioral phenotypes elicited by compounds into a simple barcode enabled identification of their mechanism of action.

In contrast to perceived nonselectivity, biochemical profiling reveals that currently available HDAC inhibitors predominantly inhibit only class I and IIb HDAC enzymes. A new pan-selective inhibitor, obtained by screening a focused library, provides an important tool for studying class IIa HDACs.

Chemical biologists are making significant progress in discovering and characterizing high-quality chemical probes. In this issue, we feature Commentary and Review Articles that capture opinions and advances at the frontiers of chemical probe research.