Discovery of tankyrase inhibiting flavones with increased potency and isoenzyme selectivity

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Cancer Biology

Background:

• Tankyrases are ADP-ribosyltransferases regulating cell proliferation and are cancer targets.
• Flavones are known tankyrase inhibitors, but more potent derivatives are needed.

Purpose of the Study:

• To discover and develop more potent and selective flavone derivatives as tankyrase inhibitors.
• To elucidate the structure-activity relationships and binding mechanisms of these inhibitors.

Main Methods:

• Structure-activity relationship studies using commercially available flavones.
• Cocrystal structure analysis of 18 hit compounds.
• Cell-based assays to assess Wnt signaling antagonism.
• Selectivity testing against homologous ADP-ribosyltransferases.

Main Results:

• Identified potent flavone derivatives with enhanced tankyrase inhibitory activity.
• Cocrystal structures revealed key interactions explaining potency and selectivity.
• The compound MN-64 demonstrated 6 nM potency against tankyrase 1 with isoenzyme selectivity.
• MN-64 effectively antagonized Wnt signaling in cell-based assays.

Conclusions:

• Flavone derivatives show promise as tankyrase inhibitors for cancer therapy.
• MN-64 is a highly potent and selective tankyrase inhibitor with Wnt signaling antagonism.
• This study provides a foundation for rational drug design targeting tankyrases.