Using sulfuramidimidoyl fluorides that undergo sulfur(VI) fluoride exchange for inverse drug discovery.

Abstract

Drug candidates that form covalent linkages with their target proteins have been under-explored compared to conventional counterparts that modulate biological function by reversible binding to proteins, in part due to concerns about off-target reactivity. But toxicity linked to off-target reactivity can be minimized by using latent electrophiles that only become activated towards covalent bond formation upon binding a specific protein. Here, we study sulfuramidimidoyl fluorides (SAFs), a class of weak electrophiles that undergo sulfur(VI) fluoride exchange (SuFEx) chemistry. We show that equilibrium binding of a SAF to a protein can allow nucleophilic attack by a specific amino acid side chain leading to conjugate formation. Sixteen small molecules, each bearing a SAF electrophile, were incubated with human cell lysate, and the protein conjugates formed were identified by affinity chromatography–mass spectrometry. This inverse drug discovery approach identified a compound that covalently binds to, and irreversibly inhibits the activity of PARP1, an important anti-cancer target in living cells.