Small-Molecule Inhibitors of the Tumor Suppressor Fhit

Abstract

The tumor suppressor Fhit and its substrate diadenosine triphosphate (Ap₃ A) are important factors in cancer development and progression. Fhit has Ap₃ A hydrolase activity and cleaves Ap₃ A into adenosine monophosphate (AMP) and adenosine diphosphate (ADP); this is believed to terminate Fhit-mediated signaling. How the catalytic activity of Fhit is regulated and how the Fhit⋅Ap₃ A complex might exert its growth-suppressive function remain to be discovered. Small-molecule inhibitors of the enzymatic activity of Fhit would provide valuable tools for the elucidation of its tumor-suppressive functions. Here we describe the development of a high-throughput screen for the identification of such small-molecule inhibitors of Fhit. Two clusters of inhibitors that decreased the activity of Fhit by at least 90 % were identified. Several derivatives were synthesized and exhibited in vitro IC₅₀ values in the nanomolar range.

Keywords: Ap3A; FRET; Fhit; enzyme inhibitors; nucleotides.