Highlights d A comprehensive degrader molecule (PROTAC) library for KRAS G12C is described d Lead compound degrades GFP-KRAS G12C in a CRBNdependent manner d Challenges and solutions for achieving endogenous KRAS G12C degradation are discussed

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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. Recently, several covalent inhibitors have been approved for cancer treatment, thus rebooting the field. In this review, we briefly reflect on the history of selective covalent targeting, and provide a comprehensive overview of emerging developments from a chemical biology stand-point. Our discussion will reflect on efforts to validate irreversible covalent ligands, expand the scope of targets, and discover new ligands and warheads. We conclude with a brief commentary of remaining limitations and emerging opportunities in selective covalent targeting.

Covalent fragment-based ligand discovery greatly facilitates the discovery of useful fragments for drug discovery and helps unveil chemical-tractable biological targets in native biological systems.

NMR resonance assignments in the vicinity of paramagnetic metals in proteins are often difficult or impossible to make using conventional 1H detected 2-D and 3-D methods due to paramagnetic line broadening. The applicability of 13Calpha{13C'} and 13C'{15N} multiple quantum coherence methods for residue-specific assignments of resonances near paramagnetic centers is described, using the Ni2+-containing enzyme acireductone dioxygenase as an example.