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

• Published in: Journal of medicinal chemistry Vol. 64; no. 13; pp. 9567 - 9576
• Main Authors: Kawaguchi, Mitsuyasu, Sekimoto, Eriko, Ohta, Yuhei, Ieda, Naoya, Murakami, Takashi, Nakagawa, Hidehiko
• Format: Journal Article
• Language: English
• Published: American Chemical Society 08-07-2021
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c00874

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.