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

Abstract

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.

• Authors: Mitsuyasu Kawaguchi, Eriko Sekimoto, Yuhei Ohta, Naoya Ieda, Takashi Murakami, Hidehiko Nakagawa
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 64 Issue 13 Pg. 9567-9576 (07 08 2021) ISSN: 1520-4804 [Electronic] United States
• PMID: 34160227 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Fluorescent Dyes
• Neoplasm Proteins
• fragile histidine triad protein
• Acid Anhydride Hydrolases

Topics

• Acid Anhydride Hydrolases (antagonists & inhibitors, genetics, metabolism)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Drug Design
• Drug Screening Assays, Antitumor
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Fluorescent Dyes (chemical synthesis, chemistry, pharmacology)
• Humans
• Molecular Structure
• Neoplasm Proteins (antagonists & inhibitors, genetics, metabolism)
• Structure-Activity Relationship