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

Melanie Rodriguez, Ashari Kannangara, Julita Chlebowicz, Radha Akella, Haixia He, Uttam K. Tambar, Elizabeth J. Goldsmith

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


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 languageEnglish (US)
Pages (from-to)1678-1684
Number of pages7
JournalACS Medicinal Chemistry Letters
Issue number10
StatePublished - Oct 13 2022


  • ATP binding pocket
  • WNK1
  • halogen bond
  • kinase inhibitor
  • small-molecule
  • structure-activity-relationship

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry


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