Affinity enhancement of polo-like kinase 1 polo box domain-binding ligands by a bivalent approach using a covalent...

Area of Science:

• Biochemistry
• Molecular Biology
• Medicinal Chemistry

Background:

• Polo-like kinase 1 (Plk1) is a crucial cell cycle regulator and a promising target for anti-cancer therapies.
• Plk1 comprises a kinase domain (KD) and a polo-box domain (PBD) involved in essential protein-protein interactions.
• Previous studies utilized a bivalent strategy with BI2536 and a PBD-binding peptide to achieve high-affinity Plk1 inhibitors.

Purpose of the Study:

• To investigate the efficacy of bivalent ligands using Wortmannin as the Plk1 KD-binding component.
• To assess the Plk1 affinity enhancement achieved with Wortmannin-based bivalent inhibitors.
• To explore the potential of these tight-binding ligands for structural analysis of full-length Plk1.

Main Methods:

• Design and synthesis of bivalent ligands incorporating Wortmannin and a PBD-binding moiety.
• Affinity measurements to quantify Plk1 binding.
• Comparison of binding affinities with previously developed BI2536-based bivalent inhibitors.

Main Results:

• Bivalent ligands with Wortmannin demonstrated significant Plk1 affinity enhancements, comparable to those achieved with BI2536.
• The developed Wortmannin-based ligands exhibited tight binding to Plk1.
• The affinity enhancements suggest potential for structural studies.

Conclusions:

• Wortmannin-based bivalent ligands are effective in achieving high-affinity inhibition of Plk1.
• These ligands represent a valuable tool for future structural investigations of Plk1.
• The bivalent approach offers a promising strategy for developing novel anti-cancer agents targeting Plk1.