Pancreatic cancer
In a mice model, administering IRAK4 reduced inflammatory signaling, after which T-cells began to attack tumors and immunotherapy became more effective. Drug target
A common concern with IRAK4 drug therapy or knockdown is if its absence would result in unbearable side effects considering IRAK4 plays an extremely central role in the TLR signalling pathway. Children with IRAK4 deficiency have been found to have decreased immunity to some specific bacterial infections yet not to viral, parasitic or other microbe infections. However, as these children enter adulthood and maternal antibodies are no longer present, susceptibility to infections becomes a rarity. In one study, no significant bacterial infections were documented in all investigated patients over the age of 14 with IRAK4 deficiency. This may mean that in later stages of life, IRAK4 inhibition could provide benefits against certain diseases while maintaining immunity.The next step in this area of research is the formation of safe IRAK4 inhibitors. There has been modest progress in the development of some potential inhibitors of IRAK4 in which their mechanism works by blocking its tyrosine gated ATP binding site. As of 2007 All potential drugs are in the early preclinical stages of development.Early-stage clinical trials of an IRAK4 inhibitor had started by 2019. Moreover, IRAK4 protein degraders have recently entered clinical trials, most notably one from Kymera Therapeutics. References
External links
IRAK4+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)
Overview of all the structural information available in the PDB for UniProt: Q9NWZ3 (Human Interleukin-1 receptor-associated kinase 4) at the PDBe-KB.
TRAF6 can polyubiquitinate IKK-γ as well as itself, which recruits TGF-β activated kinase 1 (TAK1) in order to activate its ability to phosphorylate IKK-β. These pathways both work to degrade IKKγ, which releases NFκB and free it for translocation into the nucleus. Additionally, TAK1 can activate JNK to induce a MAP kinase pathway which leads to AP-1-induced gene expression. Together, AP-1 and NFκB lead to increased cytokine transcription, adhesion molecule production, and release of second messengers of infection. Central to all of these signalling pathways is the kinase IRAK4. Results show that IRAK4 is a crucial component in an animals response to IL-1. Animals deficient in this kinase were found to be lacking in the ability to recognize viral and bacterial invaders, and were completely resistant to lethal doses of lipopolysaccharide (LPS). This is due to IRAK4s function as both a structural protein and as a kinase. Both of these functions are required for the myddosome complex formation. Additionally, IRAK4 has been shown to be absolutely essential in a TLR signalling. IRAK4 deficient mice have a profoundly impaired ability to produce IL-6, TNF-α, and IL-12 in response to TLR ligands. However it is worthy of note that despite its importance to many immune signalling pathways, IRAK4 does not appear to be involved in TCR signalling. Clinical significance
There are three components of evidence that illustrate IRAK4s involvement in TLR signalling. First, IRAK4 is the initial kinase near the TLR receptor to activate downstream effectors such as cytokines and chemokines in the inflammatory cascade.