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

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 languageEnglish (US)
JournalACS Medicinal Chemistry Letters
DOIs
StateAccepted/In press - 2022

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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