IRAK4 (Interleukin 1 Receptor Associated Kinase 4)

Despite significant progress, substantial knowledge gaps remain, particularly regarding the full spectrum of TLR signaling abnormalities across IEI subtypes. The conclusions emphasize the need for large-scale, international studies to achieve a comprehensive understanding of pathogenic mechanisms and to develop more targeted and effective therapeutic interventions for children affected by these rare disorders.

PSP-0119 is metabolically stable, retaining 71% of parent compound at 60 minutes in human liver microsomes. In summary, IRAK4 degradation via PSP-0119 as a promising therapeutic strategy for treatment of FLT3-mutant AML.

IRAK4 deficiency should be suspected in patients with early-onset recurrent bacterial infections and attenuated inflammatory response. Homozygous and compound heterozygous frameshift variants in IRAK4 gene lead to truncated IRAK4 proteins and impared innate immune signaling.

Antibiotic susceptibility testing indicated clinical potential for enrofloxacin and ciprofloxacin treatment, though resistance to azithromycin was observed. These findings demonstrate M. morganii's significant threat to bass aquaculture through metabolic disruption and immune function, meanwhile identifying potential treatment options.

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).

Compound 21 exhibited potent inhibition of cytokine secretion in cellular and whole blood phenotypic assays. Compound 21 displayed dose-dependent activity in vivo in a mouse model of collagen-induced arthritis.

We report the optimization of an imidazopyridine series of IRAK1/4/pan-FLT3 kinase inhibitors. Optimization efforts have produced key compound 31, which displays potent inhibition of IRAK1, IRAK4, and FLT3, potent activity in multiple AML tumor cell viability assays, and efficacy superior to that of approved FLT3 inhibitors in multiple mouse xenograft models of AML.

These effects were validated in AML patient cells, supporting the potential of IRAK4 inhibitors to modulate c-Myc activity and enhance combinatorial therapies. This study demonstrates that IRAK4 is a therapeutic target in AML, and that combination therapies, such as with certain GSPT1-targeting CELMoDs, will be necessary to achieve maximal clinical responses.

Clinical data from the targeted small-molecule IRAK4 inhibitor emavusertib (CA-4948) were presented, including data from the TakeAim Leukemia and TakeAim Lymphoma trials of emavusertib in myeloid and lymphoid malignancies, respectively, and preliminary data from trials of emavusertib in multiple solid tumors. The meeting closed with expert discussion of the emerging profile of IRAK4 inhibition in cancers and the potential for IRAK4 inhibition to improve outcomes across both solid and liquid tumors.

For instance, drugs like ARV-471 and ARV-110 are in advanced phases for treating metastatic breast cancer and prostate cancer, respectively, by targeting estrogen and androgen receptors. The conducted trials not only emphasize the therapeutic potential of protein degradation but also highlight the challenges associated with bioavailability, stability, and delivery mechanisms. As these clinical trials advance, they possess the potential to transform treatment paradigms, providing renewed hope for patients facing complex and refractory conditions.

Among them, HB-29 had the remarkable activity towards FLT3-WT (IC50 = 1.95 nM) and IRAK4 (IC50 = 53.72 nM), outperforming the positive control, CA-4948...Moreover, HB-29 demonstrated an acceptable bioavailability (F = 13.4 %). These findings confirm that FLT3/IRAK4 inhibitor is a promising strategy for the treatment of AML.

Validation in an independent cohort of 82 patients revealed that reduced expression of these genes correlated with markers of advanced disease, including lower hemoglobin levels, lower neutrophil counts, altered cytogenetics, and higher bone marrow blast percentages. These findings underscore the critical role of immune dysregulation in MDS progression and highlight novel therapeutic opportunities within the innate immunity pathway for tailored interventions.