Exploiting human fucosyltransferase 8 allostery with a covalent inhibitor for core fucosylation suppression

Area of Science:

• Biochemistry
• Drug Discovery
• Cancer Biology

Background:

• Core fucosylation, mediated by fucosyltransferase 8 (FUT8), is crucial in cancer progression, immune evasion, and drug resistance.
• Developing selective FUT8 inhibitors is challenging due to the conserved substrate specificity among fucosyltransferases.

Purpose of the Study:

• To identify novel therapeutic targets and develop selective inhibitors for FUT8.
• To explore allosteric inhibition strategies for targeting FUT8 activity.

Main Methods:

• Structure-based drug design utilizing high-throughput screening and crystallographic studies.
• Development of a covalent inhibitor, CAIF, targeting an allosteric site on FUT8.
• In vitro cellular assays to evaluate CAIF's efficacy and cytotoxicity.

Main Results:

• Discovery of a previously unrecognized allosteric site on FUT8.
• CAIF, a novel covalent inhibitor, was designed to target lysine K216 within the allosteric site.
• CAIF demonstrated minimal cytotoxicity, inhibited core fucosylation, and reduced cancer cell invasion.

Conclusions:

• CAIF represents a promising lead compound for FUT8-targeted cancer therapies.
• This study provides a novel framework for targeting glycosyltransferases via allosteric and covalent inhibition.
• Targeting FUT8 allosterically offers a new avenue for developing selective inhibitors with reduced toxicity.