2. Academic Validation
  3. Examination of Noncanonical Kinase Hinge Binders Leads to Thiadiazoles as Potent IRAK4 Inhibitors

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

Affiliation

  • 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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