Recent Advances in the Discovery of Small Molecule Inhibitors of Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) as a Therapeutic Target for Inflammation and Oncology Disorders

Abstract

IRAK4, a serine/threonine kinase, plays a key role in both inflammation and oncology diseases. Herein, we summarize the compelling biology surrounding the IRAK4 signaling node in disease, review key structural features of IRAK4 including selectivity challenges, and describe efforts to discover clinically viable IRAK4 inhibitors. Finally, a view of knowledge gained and remaining challenges is provided.

Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

“…In humans, mutations in IRAK-4 have been associated with susceptibility to bacterial infections. Small molecule IRAK-4 inhibitors are in clinical development and have been facilitated by the discovery of the crystal structure of IRAK-4 (Chaudhary et al, 2015). A naturally occurring compound lancemaside C inhibits macrophage activation induced by LPS via TLR through inhibition of IRAK-4 (Joh and Kim, 2010).…”

Discovery of 5-Amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide Inhibitors of IRAK4

“…Potency loss was also observed for 27 and 28 compared with 18 and 19, albeit to a lesser extent. It was generally observed that the CHF 2 analogues offered higher intrinsic IRAK4 potency and comparable membrane permeability compared with the corresponding CF 3 analogues, as seen with (1R,2S)-cyclohexane-1,2-diamine, (1R,2S)-2-hydroxycyclohexylamine, and piperazine groups on the pyrazolopyrimidine ring (18,19,25,26,27, and 28 in Table 4). …”

Inhibiting the Inflammasome: A Chemical Perspective

“…Despite few specific inhibitors of IRAK1 that currently exist, a number of potent and selective small molecule inhibitors for IRAK4 have been developed. 167 It would be interesting to evaluate some of the new generation IRAK4 inhibitors as small molecule therapeutics against early phase, acute NLRP3 inflammasome activation.…”