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Targeted covalent inhibitors (TCIs) are actively pursued in drug discovery due to their prolonged target engagement and clinical efficacy. Although kinetic parameters provide a path to their optimizat...

Dysregulated reactive oxygen species (ROS) are implicated in various diseases, positioning NADPH oxidase enzymes (NOXs) as attractive therapeutic targets. However, progress in tool compound discovery ...

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Grants from the National Institutes of Health come with additional money for overhead. Proposed funding cuts would leave colleges with large budget gaps.

The move halts a large slice of money for most universities and research institutions virtually overnight, imperiling vital research in everything from cancer to heart disease.

The move halts a large slice of money for most universities and research institutions virtually overnight, imperiling vital research in everything from cancer to heart disease.

Binding multiple sites within proteins with bivalent compounds is a strategy for developing uniquely active agents. A new class of dual-site inhibitors has emerged targeting the epidermal growth factor receptor (EGFR) anchored to both the orthosteric (ATP) and allosteric sites. Despite proof-of-concept successes, enabling selectivity against oncogenic activating mutations has not been achieved and classifying these inhibitors among kinase inhibitors remains underexplored. This study investigates the structure–activity relationships, binding modes, and biological activity of ATP-allosteric bivalent inhibitors (AABIs). We find that AABIs selectively inhibit drug-resistant EGFR mutants (L858R/T790M and L858R/T790M/C797S) by anchoring a methyl isoindolinone moiety along the αC-helix channel of the allosteric site. In contrast, related Type I1/2 inhibitors target wild-type EGFR but are less effective against resistant mutants. This shift in selectivity demonstrates that mutant-selective AABIs classify as “Type V” bivalent inhibitors.

Summary:. Research on precancers, as defined as at-risk tissues and early lesions, is of high significance given the effectiveness of early intervention. We discuss the need for risk stratification to...