Synthesis and Structural Characterization of Novel Trihalo-sulfone Inhibitors of WNK1
Year: 2022
Type: article
Abstract: With No lysine (K) [WNK] kinases are structurally unique serine/threonine protein kinases that have therapeutic potential for blood pressure regulation and cancer. A novel class of trihalo-sulfone compounds was identified by high-throughput screening. Trihalo-sulfone 1 emerged as an effective inhibitor of WNK1 with an IC 50 value of 1.6 μM. Herein, we define chemical features necessary for inhibition of WNK1 using chemical synthesis and X-ray crystallography. Analogues that probed the role of specific functional groups to the inhibitory activity were synthesized. X-ray structures of trihalo-sulfone 1 and a second trihalo-sulfone 23 bound to WNK1 revealed active site binding to two of the three previously defined canonical inhibitor binding pockets as well as a novel binding site for the trihalo-sulfone moiety. The elucidation of these novel interaction sites may allow for the strategic design of even more selective and potent WNK inhibitors.
Source: ACS Medicinal Chemistry Letters
Institution: The University of Texas Southwestern Medical Center
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
Funders: Alfred P. Sloan Foundation, Welch Foundation, American Heart Association, Cancer Prevention and Research Institute of Texas, University of Texas Southwestern Medical Center, W. W. Caruth, Jr. Foundation, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases
OpenAlex ID: W4297090317