Small Molecule Screening Strategies from Lead Identification to Validation.

Festa, F., Labaer, J. Kinase inhibitor screening in self-assembled human protein microarrays.

Target 2035 - update on the quest for a probe for every protein.

Twenty years after the publication of the first draft of the human genome, our knowledge of the human proteome is still fragmented. The challenge of translating the wealth of new knowledge from genomics into new medicines is that proteins, and not genes, are the primary executers of biological function. Therefore, much of how biology works in health and disease must be understood through the lens of protein function.

Correction: Fragment-based covalent ligand discovery.

[This corrects the article DOI: 10.1039/D0CB00222D.].

Fragment-based covalent ligand discovery.

Targeted covalent inhibitors have regained widespread attention in drug discovery and have emerged as powerful tools for basic biomedical research. Fueled by considerable improvements in mass spectrometry sensitivity and sample processing, chemoproteomic strategies have revealed thousands of proteins that can be covalently modified by reactive small molecules. Fragment-based drug discovery, which has traditionally been used in a target-centric fashion, is now being deployed on a proteome-wide scale thereby expanding its utility to both the discovery of novel covalent ligands and their cognate protein targets.

Critical Assessment of Targeted Protein Degradation as a Research Tool and Pharmacological Modality.

Small molecules continue to dominate drug discovery because of their ease of use, lower cost of manufacturing, and access to intracellular targets. However, despite these advantages, small molecules are more likely to fail in clinical trials compared with biologicals and their development remains limited to a small subset of disease-relevant 'druggable' targets. Targeted protein degradation has recently emerged as a novel pharmacological modality that promises to overcome small molecule limitations whilst retaining their key advantages.

Exploring Targeted Degradation Strategy for Oncogenic KRAS.

KRAS is the most frequently mutated oncogene found in pancreatic, colorectal, and lung cancers. Although it has been challenging to identify targeted therapies for cancers harboring KRAS mutations, KRAS can be targeted by small-molecule inhibitors that form covalent bonds with cysteine 12 (C12). Here, we designed a library of C12-directed covalent degrader molecules (PROTACs) and subjected them to a rigorous evaluation process to rapidly identify a lead compound.

Recent Advances in Selective and Irreversible Covalent Ligand Development and Validation.

Some of the most widely used drugs, such as aspirin and penicillin, are covalent drugs. Covalent binding can improve potency, selectivity, and duration of the effects, but the intrinsic reactivity represents a potential liability and may result in idiosyncratic toxicity. For decades, the cons were believed to outweigh the pros, and covalent targeting was deprioritized in drug discovery.

From Glioblastoma to Hepatitis C: It's a Metabolism Thing.

Every month the editors of Cell Chemical Biology bring you highlights of the most recent chemical biology literature. Our November 2016 selection includes the discovery that cholesterol supply is a weak link in glioblastoma metabolism and the finding that nuclear hormone receptors are in the center of the complicated relationship we have with the hepatitis C virus.

RAF Inhibitors, Fishing Bacterial Transporters Out of Metagenomes, and Yeast-Based, Industrial Scale Production of Isoprenoids.

Every month the editors of Cell Chemical Biology bring you highlights of the most recent chemical biology literature. Our October 2016 selection includes systematic structural, biochemical, and cellular characterization of B-RAF inhibitors; connecting bacterial transporters with their physiologically relevant ligands; and rewiring yeast metabolism for industrial scale production of isoprenoids.

Biasing Opioid Receptors and Cholesterol as a Player in Developmental Biology.

Every month the editors of Cell Chemical Biology bring you highlights of the most recent chemical biology literature. Our September 2016 selection includes the discovery of PZM21, a μOR biased agonist with minimal side effects, and the role of cholesterol in Hedgehog signaling pathway.

Stem Cell Hydrogel, Jump-Starting Zika Drug Discovery, and Engineering RNA Recognition.

Every month the editors of Cell Chemical Biology bring you highlights of the most recent chemical biology literature that impressed them with creativity and potential for follow up work. Our August 2016 selection includes a description of hydrogels with self-tunable stiffness that are used to profile lipid metabolites during stems cell differentiation, a look at whether we can find a drug repurposing solution to Zika virus infection, and an engineered RNA recognition motif (RRM).