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

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).