Examination of Noncanonical Kinase Hinge Binders Leads to Thiadiazoles as Potent IRAK4 Inhibitors

  • ACS Med Chem Lett. 2025 Dec 16;17(1):175-182. doi: 10.1021/acsmedchemlett.5c00602.
Stephen E Ammann  1 ,  Gediminas Brizgys  1 ,  Ryan D Ferrao  1 ,  Nathan E Wright  1 ,  Prasenjit Kumar Mukherjee  1 ,  Elizabeth M Bacon  1 ,  Elbert Chin  1 ,  Chienhung Chou  1 ,  Jeromy J Cottell  1 ,  Angela Hammond  1 ,  Marilyn S Ndukwe  1 ,  Grace Y Park  1 ,  Marina E Shatskikh  1 ,  Kimberly Suekawa-Pirrone  1 ,  Matthew R Warr  1 ,  Zheng-Yu Yang  1 ,  Sheila M Zipfel  1 ,  James G Taylor  1
Affiliations
  • 1. Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States.
PMID: 41531974 DOI: 10.1021/acsmedchemlett.5c00602
Abstract

A hallmark of most known small-molecule orthosteric kinase inhibitors is hydrogen-bonding to the hinge-region of the kinase to mimic the hinge interaction of adenine. Herein we report our studies on deviation from canonical hinge-binders in the context of IRAK4 inhibitors. Small-molecule inhibitors of IRAK4 have generated interest as potential treatments for inflammatory diseases. Notably, in our discovery efforts we identified pyridinyl-thiadiazoles as noncanonical hinge-binders. X-ray structural evidence supports that the thiadiazole moiety engages in a rare intermolecular noncovalent sulfur-oxygen interaction. This thiadiazole series, exemplified by compounds 19 and 22, has shown promise for potent, selective, orally bioavailable IRAK4 inhibitors.

Keywords
Interleukin-1 receptor-associated kinase 4 (IRAK4); noncanonical kinase hinge-binder; noncovalent sulfur oxygen interaction; thiadiazole.
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