Synthesis of Fluorescent Probes Targeting Tumor-Suppressor Protein FHIT and Identification of Apoptosis-Inducing FHIT Inhibitors

For the early diagnosis of cancer, leading to a better chance of
full recovery, marker genes whose expression is already altered in
precancerous lesions are desirable, and the tumor-suppressor gene FHIT is one candidate. The gene product, FHIT protein, has
a unique dinucleoside triphosphate hydrolase (AP3Aase)
activity, and in this study, we designed and synthesized a series
of FHIT fluorescent probes utilizing this activity. We optimized the
probe structure for high and specific reactivity with FHIT and applied
the optimized probe in a screening assay for FHIT inhibitors. Screening
of a compound library with this assay identified several hits. Structural
development of a hit compound afforded potent FHIT inhibitors. These
inhibitors induce apoptosis in FHIT-expressing cancers via caspase
activation. Our results support the idea that FHIT binders, no matter
whether inhibitors or agonists of AP3Aase activity, might
be promising anticancer agents.