Mammalian cryptochromes regulate sleep and metabolism as components of the circadian clock. In this issue of Cell Chemical Biology, Miller et al. (2020a) use phenotypic chemical screens to identify selective modulators of two cryptochrome isoforms. Binding specificity depends on conformational patterning of the ligand-binding pocket and a disordered C-terminal domain.

N-acyl amino acids are a class of biologically active lipids that control thermogenesis, and their biosynthesis is facilitated by PM20D1. In this issue of Cell Chemical Biology, Kim et al. (2020) identify a lipoprotein-albumin network in the blood that regulates physiological levels of N-acyl amino acids.

In this issue of Cell Chemical Biology, Hong et al. (2020) use in situ chemoenzymatic labeling to discover that fucosylation of the Wnt co-receptor LRP6 induces its endocytosis and downregulates Wnt/β-catenin signaling. Their findings reveal a glycosylation-based mechanism for regulating Wnt signaling that could be targeted in cancer.

K-RAS is known as the most frequently mutated oncogene. However, the development of conventional K-RAS inhibitors has been extremely challenging, with a mutation-specific inhibitor reaching clinical trials only recently. Targeted proteolysis has emerged as a new modality in drug discovery to tackle undruggable targets. Our laboratory has developed a system for targeted proteolysis using peptidic high-affinity

Infections with Salmonella enterica pose a challenge for antibiotic treatment. In this issue of Cell Chemical Biology, Tsai et al. use a chemical genomics approach to identify dephostatin as an inhibitor of intracellular Salmonella virulence in vitro and in vivo by targeting the two-component systems SsrA-SsrB and PmrB-PmrA.

In this issue of Cell Chemical Biology, Hu et al. (2020) demonstrate that chlorcyclizine blocks HCV fusion by targeting the putative fusion peptide on the viral envelope glycoprotein E1. The study provides new insights into the viral fusion machinery, presenting an opportunity to study novel antivirals against HCV.

In this issue of Cell Chemical Biology, Pisa et al. (2020) find that haploid and diploid cells differentially develop resistance to the CENP-E inhibitor GSK923295. The results highlight the power of tumor cells to evade growth inhibition and potentially inform the design of next-generation CENP-E drugs to overcome resistance.