@article{daf4214d27d4467dbfa4d5e32dddc096,
title = "Synthesis and Structural Characterization of Novel Trihalo-sulfone Inhibitors of WNK1",
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 IC50 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.",
keywords = "ATP binding pocket, WNK1, halogen bond, kinase inhibitor, small-molecule, structure-activity-relationship",
author = "Melanie Rodriguez and Ashari Kannangara and Julita Chlebowicz and Radha Akella and Haixia He and Tambar, {Uttam K.} and Goldsmith, {Elizabeth J.}",
note = "Funding Information: Financial support was provided by the American Heart Association 16SA285300002 and 14GRNT20500035 (E.J.G.), Cancer Prevention and Research Institute of Texas (RP190421 to E.J.G. and U.K.T.), Welch Foundation (I-2100-20220331 to E.J.G., I-1748 to U.K.T.), W. W. Caruth, Jr. Endowed Scholarship (U.K.T.), Sloan Research Fellowship (U.K.T.), Bonnie Bell Harding Professorship in Biochemistry (U.K.T.), NIH-DK (DK110358 to E.J.G.), and NIH-NCI (T32CA124334 to M.R.). We thank Clinton Taylor and Melanie Cobb for the gOSR1 peptide, Shuguang Wu and Bruce Posner for help with HTS data collection, and Anwu Zhou and Prema Mallipeddi for HTS data analysis. Crystallographic studies were coordinated by Diana Tomchick in the UT Southwestern Structural Biology Laboratory. Results shown in this report were derived from work performed at Argonne National Laboratory, Structural Biology Center (SBC), at the Advanced Photon Source. The SBC is operated by the U Chicago Argonne, LLC, for the U.S. Department of Energy, Office of Biological and Environmental Research under contract DE-AC02-06CH11357. We acknowledge Dr. Vincent Lynch (manager of the X-ray Diffraction Lab at UT Austin) for X-ray structural analysis of trihalo-sulfone 1 . Finally, we thank our diverse group of laboratory members for creating an environment that supports our scientific endeavors. Publisher Copyright: {\textcopyright} 2022 American Chemical Society.",
year = "2022",
month = oct,
day = "13",
doi = "10.1021/acsmedchemlett.2c00216",
language = "English (US)",
volume = "13",
pages = "1678--1684",
journal = "ACS Medicinal Chemistry Letters",
issn = "1948-5875",
publisher = "American Chemical Society",
number = "10",
}