IRAK-4 Inhibitors for Inflammation

Abstract

Interleukin-1 receptor-associated kinases (IRAKs) are key components in the signal transduction pathways utilized by interleukin-1 receptor (IL-1R), interleukin-18 receptor (IL-18R), and Toll-like receptors (TLRs). Out of four members in the mammalian IRAK family, IRAK-4 is considered to be the “master IRAK”, the only family member indispensable for IL-1R/TLR signaling. In humans, mutations resulting in IRAK-4 deficiency have been linked to susceptibility to bacterial infections, especially recurrent pyogenic bacterial infections. Furthermore, knock-in experiments by several groups have clearly demonstrated that IRAK-4 requires its kinase activity for its function. Given the critical role of IRAK-4 in inflammatory processes, modulation of IRAK-4 kinase activity presents an attractive therapeutic approach for the treatment of immune and inflammatory diseases. The recent success in the determination of the 3-dimensional structure of the IRAK-4 kinase domain in complex with inhibitors has facilitated the understanding of the mechanistic role of IRAK-4 in immunity and inflammation as well as the development of specific IRAK-4 kinase inhibitors. In this article, we review the biological function of IRAK-4, the structural characteristics of the kinase domain, and the development of small molecule inhibitors targeting the kinase activity. We also review the key pharmacophores required for several classes of inhibitors as well as important features for optimal protein/inhibitor interactions. Lastly, we summarize how these insights can be translated into strategies to develop potent IRAK-4 inhibitors with desired properties as new anti-inflammatory therapeutic agents.

Triggering of toll-like receptor-4 in human multiple myeloma cells promotes proliferation and alters cell responses to immune and chemotherapy drug attack

“…[11][12][13] Thus, activation of MAPK p38, ERK p44erk-1 and p42erk-2 by IL-18 was detected in a human NK cell line in previous studies. [14][15][16][17] However, little is known of the secretion and regulation of IL-18 in MM cells. In this study, we found that LPS induced IL-18 secretion and activated MAPK and NFκB signaling in MM.1S and ARP-1 cells simultaneously.…”

Immune Complex-Mediated Cell Activation from Systemic Lupus Erythematosus and Rheumatoid Arthritis Patients Elaborate Different Requirements for IRAK1/4 Kinase Activity across Human Cell Types

“…Recruitment of IRAK4 and IRAK1 to the MyD88-signaling complex elaborates NF-kB-dependent inflammation (2,3). MyD88 is also coupled to IFN regulatory factors (IRFs) that mediate differential expression of specific cytokines, depending on the TLR/IL-1R signaling pathway (4,5).…”

“…It is clear that although similarities in IRAK4 activity exist between human and mouse, there are important differences as well. Mice deficient for IRAK4 are severely impaired in their cellular responses to IL-1, IL-18, and most TLR ligands, sharing an overlapping phenotype with IRAK4-deficient human patients (3). However, although IRAK4-deficient mice display broad susceptibility to viral and bacterial infections, IRAK4-deficient human patients exhibit a narrow infectious phenotype, limited primarily to pyogenic bacterial infections at an early age (6,7).…”

A Coding IRAK2 Protein Variant Compromises Toll-like receptor (TLR) Signaling and Is Associated with Colorectal Cancer Survival

“…Furthermore, the data presented here also warrant the inclusion of IRAK2 rs35060588 in future genetic association studies and the exploration of its functional phenotype in human carriers. IRAK inhibitors are already under development for the treatment of inflammation and B cell malignancies (6,35). In a dawning age of individualized medicine and straightforward sequence acquisition, broader studies into the genetic predisposition of infectious, autoimmune, and malignant diseases will help to characterize the potential value of rs35060588 and potentially other IRAK2 variants as biomarkers of disease or points of therapeutic intervention (e.g.…”