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.
Original language | English (US) |
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Pages (from-to) | 1678-1684 |
Number of pages | 7 |
Journal | ACS Medicinal Chemistry Letters |
Volume | 13 |
Issue number | 10 |
DOIs | |
State | Published - Oct 13 2022 |
Keywords
- ATP binding pocket
- WNK1
- halogen bond
- kinase inhibitor
- small-molecule
- structure-activity-relationship
ASJC Scopus subject areas
- Biochemistry
- Drug Discovery
- Organic Chemistry