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. 2025 Jul 28:131:118333.
doi: 10.1016/j.bmc.2025.118333. Online ahead of print.

Generation of a potent & selective series of IRAK4 inhibitors based on a structure based, hybridization approach

Ina Terstiege  1 , Anna Aagaard  2 , Kristina Berggren  3 , James Bird  4 , Iain A Cumming  5 , Sam D Groombridge  5 , Lotta Hidestål  3 , Petra Johannesson  3 , Pernilla Korsgren  6 , Karl-Johan Leuchowius  7 , Sara Lundqvist  7 , James S Scott  5 , Yafeng Xue  2 , Sébastien L Degorce  5
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Generation of a potent & selective series of IRAK4 inhibitors based on a structure based, hybridization approach

Ina Terstiege et al. Bioorg Med Chem. .

Abstract

IRAK4 inhibitors are of high interest as treatment for not only inflammatory and autoimmune diseases, but also in the field of oncology. Despite extensive research in the IRAK4 area and progression of several inhibitors into clinical trials, no IRAK4 inhibitor has yet reached the market. In this article, we describe the development of a highly potent and selective IRAK4 lead compound 5e, starting from Astellas AS2444697 (1a). The work includes identification of the pyrazole-pyridine substituent in compound 1g, binding towards the gatekeeper region of IRAK4, followed by a structure-guided scaffold hybridization that led to 5a. Subsequent optimization of substituents of the indazole scaffold yielded 5e, which exhibits a 10-fold improvement in IRAK4 cell potency and higher off-target selectivity compared to AS244697 (1a).

Keywords: Hybridization; IRAK4 inhibitor; Inflammation.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ina Terstiege reports a relationship with AstraZeneca that includes: employment and equity or stocks. Anna Aagaard reports a relationship with AstraZeneca that includes: employment and equity or stocks. Kristina Berggren reports a relationship with AstraZeneca that includes: employment and equity or stocks. James Bird reports a relationship with AstraZeneca that includes: employment and equity or stocks. Iain A. Cumming reports a relationship with AstraZeneca that includes: employment and equity or stocks. Lotta Hidestal reports a relationship with AstraZeneca that includes: employment and equity or stocks. Petra Johannesson reports a relationship with AstraZeneca that includes: employment and equity or stocks. Pernilla Korsgren reports a relationship with AstraZeneca that includes: employment and equity or stocks. Karl-Johan Leuchowius reports a relationship with AstraZeneca that includes: employment and equity or stocks. Sara Lundqvist reports a relationship with AstraZeneca that includes: employment and equity or stocks. James S. Scott reports a relationship with AstraZeneca that includes: employment and equity or stocks. Yafeng Xue reports a relationship with AstraZeneca that includes: employment and equity or stocks. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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