covalent inhibitor prodrugs
Covalent inhibitors (CIs) have emerged as a crucial class of small-molecule therapeutics, accounting for roughly 30% of all active drugs on the market. These molecules are rationally designed with electrophilic groups (warheads) positioned to react swiftly with nucleophilic residues near protein binding site, effectively preventing dissociation. Despite the therapeutic potential, offering prolonged target engagement and enhanced potency, their highly electrophilic warheads can react indiscriminately, limiting their formulation as antibody–drug conjugate (ADC) payloads. This limitation can result in significant toxicity, including hepatotoxicity, immunogenic responses, and disruption of essential biological processes.
We engineer masked acrylamide based warheads that stay inert during systemic circulation and conjugation, then self‑immolate inside diseased cells via a rapid, biocompatible bond‑cleaving reaction. By installing a removable “safety cap”, we transform an otherwise promiscuous Michael acceptor into a precision, on‑demand electrophile. By coupling the mask to enzyme‑cleavable motifs (e.g., cathepsin‑B‑sensitive val‑cit or penicillin‑G amidase substrates) we restrict activation to tumour microenvironments where these proteases are abundant, achieving exquisite spatial control. With the electrophile dormant, we can load CIs onto monoclonal antibodies without fouling lysine, cysteine, or serine residues, opening the door to CI‑based ADCs that combine the targeting accuracy of biologics with the sustained knock‑down of covalent chemistry.
This platform shifts covalent inhibition from a liability‑ridden niche to a broadly deployable modality, expanding the therapeutic index, tackling previously “undruggable” targets, and giving medicinal chemists a programmable switch for electrophilic potency. We are building a library of masked warheads tuned for reaction rate, stability, and trigger specificity; integrating them into ADCs and small‑molecule conjugates; and validating efficacy in animal models of resistant cancers. By uniting the precision of prodrug activation with the staying power of covalent drugs, we aim to deliver safer, longer‑lasting therapies that meet the toughest challenges head‑on.
We engineer masked acrylamide based warheads that stay inert during systemic circulation and conjugation, then self‑immolate inside diseased cells via a rapid, biocompatible bond‑cleaving reaction. By installing a removable “safety cap”, we transform an otherwise promiscuous Michael acceptor into a precision, on‑demand electrophile. By coupling the mask to enzyme‑cleavable motifs (e.g., cathepsin‑B‑sensitive val‑cit or penicillin‑G amidase substrates) we restrict activation to tumour microenvironments where these proteases are abundant, achieving exquisite spatial control. With the electrophile dormant, we can load CIs onto monoclonal antibodies without fouling lysine, cysteine, or serine residues, opening the door to CI‑based ADCs that combine the targeting accuracy of biologics with the sustained knock‑down of covalent chemistry.
This platform shifts covalent inhibition from a liability‑ridden niche to a broadly deployable modality, expanding the therapeutic index, tackling previously “undruggable” targets, and giving medicinal chemists a programmable switch for electrophilic potency. We are building a library of masked warheads tuned for reaction rate, stability, and trigger specificity; integrating them into ADCs and small‑molecule conjugates; and validating efficacy in animal models of resistant cancers. By uniting the precision of prodrug activation with the staying power of covalent drugs, we aim to deliver safer, longer‑lasting therapies that meet the toughest challenges head‑on.