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

• Published in: ACS medicinal chemistry letters 2022-10, Vol.13 (10), p.1678-1684
• Main Authors: Rodriguez, Melanie, Kannangara, Ashari, Chlebowicz, Julita, Akella, Radha, He, Haixia, Tambar, Uttam K., Goldsmith, Elizabeth J.
• Format: Article
• Language: English
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.2c00216

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.