Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 13, Issue 10, Pages 1678-1684Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.2c00216
Keywords
WNK1; kinase inhibitor; structure-activity-relationship; small-molecule; halogen bond; ATP binding pocket
Categories
Funding
- American Heart Association [16SA285300002, 14GRNT20500035]
- Cancer Prevention and Research Institute of Texas [RP190421]
- Welch Foundation [I-2100-20220331, I-1748]
- Sloan Research Fellowship
- Bonnie Bell Harding Professorship in Biochemistry [DK110358]
- NIH-NCI [T32CA124334]
- UT Southwestern Structural Biology Laboratory
- U.S. Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH11357]
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A new class of trihalo-sulfone compounds was identified as effective inhibitors of WNK1, and the necessary chemical features for inhibition of WNK1 were determined through chemical synthesis and X-ray crystallography.
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 mu M. 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.
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