Prodrugs are effective tools in overcoming drawbacks typically associated with drug properties in vivo.  Protecting group strategies are readily utilized in prodrug design wherein a stimulus-responsive trigger is appended to the drug, rendering it inactive until where desired.  This work details the development of a prodrug of the canonical HDAC broad-spectrum inhibitor suberoylanilide hydroxamic acid, SAHA.  Although hydroxamic acids are utilized universally as metal binding groups in the development of metalloenzyme inhibitors, they are considered poor pharmacophores due in part to poor cell permeability, hydrolytic instability and susceptibility to glucoronidation, leading to reduced activity in vivo.  Alkylation of hydroxamates has been shown to enhance overall aqueous stability, cellular permeability and will likely prevent glucoronidation issues.  We have developed a prodrug of SAHA by appending a promoiety sensitive only to nucleophilic thiols to the hydroxamic acid we term SAHA-TAP (Thiol Activated Prodrug).  Upon the incubation of SAHA-TAP with HDAC, the thiol moiety of a conserved cysteine residue in the catalytic pocket of HDAC nucleophilically attacks the promoiety, initiating a cascade reaction that leads to the release of the inhibitor SAHA.  Proteomic mass spectrometry validates that the cysteine residue of interest is covalently tagged with the TAP promoiety, which subsequently leads to the release of SAHA.  This strategy represents an original prodrug design with a dual-mode of action for HDAC inhibition with enhanced therapeutic potential.

Dual-mode HDAC prodrug induces an active site covalent modification with subsequent inhibitor release

248th National Meeting (2014)

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