Synthesis and Structural Characterization of Novel Trihalo-sulfone Inhibitors of WNK1

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Structural Biology

Background:

• With No lysine (K) [WNK] kinases are key regulators with therapeutic potential in hypertension and oncology.
• Identifying potent and selective WNK kinase inhibitors is a significant challenge.

Purpose of the Study:

• To define the chemical features required for WNK1 inhibition.
• To elucidate the binding interactions of novel trihalo-sulfone compounds with WNK1.
• To guide the rational design of improved WNK inhibitors.

Main Methods:

• High-throughput screening to identify initial inhibitors.
• Chemical synthesis of trihalo-sulfone analogues.
• X-ray crystallography to determine WNK1-inhibitor complex structures.

Main Results:

• Trihalo-sulfone 1 demonstrated potent WNK1 inhibition (IC50 = 1.6 μM).
• Structural studies revealed binding to canonical pockets and a novel site for the trihalo-sulfone moiety.
• Structure-activity relationships were established for key functional groups.

Conclusions:

• Novel trihalo-sulfones are effective WNK1 inhibitors.
• The identified binding modes provide insights into WNK kinase inhibition.
• These findings facilitate the development of next-generation WNK inhibitors for therapeutic applications.