Volume 18 Issue 6, June 2022

Despite well-established tumorigenic roles of KRAS mutants, targeting their smooth surfaces was a challenge, which was overcome through the development of G12C-specific covalent inhibitors. A new study shows that optimizing non-covalent interactions with a cryptic pocket produces remarkable potency for another hotspot mutation.

Precision oncology requires an understanding of the genes and pathways that dictate therapeutic response. Through specialized analysis of drug sensitivity patterns across hundreds of genomically annotated cancer cell lines, specific and actionable drivers of intrinsic resistance have been identified.

Microproteins can be generated by a shift in the reading frame during translation. A chemoproteomics approach led to the identification of MINAS-60 as an alternative microprotein that regulates the assembly of the pre-60S ribosome.

The discovery of long-existing terpenoid biosynthetic pathways in soft corals changes the way specialized metabolism in animals is thought about, and opens unprecedented access to the largely untapped treasure trove of medicinal marine natural products.

This Review discusses how combining computational modeling with multiparametric profiling of small-molecule effects can accelerate and expand the search for new and unconventional antibacterial strategies.

The use of NMR spectroscopy and development of a cellular BRET KRAS engagement assay revealed that noncovalent ligands can access the switch-II pocket of KRAS hotspot mutants.

A patient-derived colorectal organoid drug screening platform was developed revealing an association between paclitaxel sensitivity and CHFR, a member of the spindle checkpoint component.

Identification of genes associated with resistance to hundreds of cancer therapeutics enabled the discovery of the serine hydrolases MGLL and CES1 as modifiers of sensitivity to GSK-J4 via direct enzymatic modification.

A genetically encoded metabolic glycan labeling (GeMGL) method based on an orthogonal engineered enzyme–unnatural sugar pair was developed for cell-type-specific glycan labeling in cells and living mice.

A modular approach for synthesis of proteoglycan glycoconjugates relies on bioorthogonal glycosylation of alkyne-tagged core proteins with azide-tagged glycosaminoglycans to enable the analysis of their functional roles on mammalian cell surfaces.

Cao et al. develop a chemoproteomic pipeline to identify nascent unannotated alt-proteins and show that cell-cycle-regulated alt-protein MINAS-60 is a checkpoint inhibitor of pre-60S assembly.

Elucidation of the biosynthetic pathway of the γ-butyrolactone core structure of the furanolide natural product cyanobacterin reveals a carbon–carbon bond-forming cascade that features an enzyme catalyzing a Morita–Baylis–Hillman reaction.

Rather than relying on microbial symbionts, certain corals themselves encode terpene cyclases that produce the eunicellane precursor of defensive terpenes, while the sequences of widespread related cyclase genes indicate a potential ancient origin.

Marine natural products are often made by symbiotic microbes, but octocorals encode their own terpene cyclases that share features with bacterial versions and produce terpenoid precursors, including the coral-exclusive capnellane scaffold.

The cryo-EM structure of the Csy–dsDNA–AcrIF5 complex and biochemical analysis revealed that five AcrIF5 molecules bind to one Csy–dsDNA complex, destabilizing the helical bundle domain of Cas8f and preventing recruitment of Cas2/3.