ACS Chemical Biology, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 26, 2024

Recent advances in the field of translational chemical biology use diverse "proximity-inducing" synthetic modalities to elicit new modes "event driven" pharmacology. These include mechanisms targeted protein degradation and immune clearance pathogenic cells. Heterobifunctional "chimeric" compounds like Proteolysis TArgeting Chimeras (PROTACs) Antibody Recruiting Molecules (ARMs) leverage these mechanisms, respectively. Both systems function through formation reversible "ternary" or higher-order biomolecular complexes. Critical are key parameters, such as bifunctional molecule affinity for endogenous proteins, target residence time, turnover. To probe mechanism enhance function, covalent approaches have been developed kinetically stabilize ternary electrophilic PROTACs Covalent Immune Recruiters (CIRs), latter designed uniquely enforce cell-cell induced proximity. Inducing proximity is associated with challenges arising from a combination steric and/or mechanical based destabilizing forces on complex. factors can attenuate complexes driven by high bifunctional/proximity inducing molecules. This Account describes initial efforts our lab address using CIR strategy antibody recruitment receptor engineered T cell model ARMs form serum antibodies surface antigens tumor cells that subsequently engage via Fc receptors. Binding clustering receptors trigger killing cell. We applied convert chimeras, which "irreversibly" recruit chimeras electrophile preorganization kinetic effective molarity achieve fast selective engagement complex protein, e.g., antibody. Importantly, proceed binding site amino acids beyond cysteine. demonstrated striking functional enhancements compared noncovalent ARM analogs assays. revealed this enhancement was fact due increased stability

Language: Английский