IRAK-4 (interleukin-1 receptor-associated kinase 4) is a protein kinase involved in signal transduction of innate immune response from toll-like receptors. Specifically, it also supports signal transduction from T cell receptors. Besides, IRAK-4 is a family of IL-1 receptors (IL-1Rs) and toll-like receptors (TLRs). Moreover, IRAK-4 plays an important role in the initiation and control of the innate immune response. When one of these pathways is stimulated, the cells release pro-inflammatory signals and trigger innate immunity. Therefore, the regulation of IRAK-4 activity has emerged as a promising strategy to control the inflammatory response. IRAK-4 is an attractive target for the treatment of inflammatory autoimmune diseases such as rheumatoid arthritis (RA) and other related diseases. Furthermore, IRAK-4 is an important part of animal response to IL-1 and acts as both a structural protein and a kinase. HS271 is a highly potent, orally active, and selective IRAK4 inhibitor.
HS271 is a highly potent, orally active, and selective IRAK4 inhibitor.
How does HS271 work on the target? Let’s study it together. In the beginning, HS271 is a selective IRAK4 inhibitor with an IC50 of 7.2 μM. Meanwhile, HS271 exhibits superior enzymatic and cellular activities, as well as excellent pharmacokinetic properties.
In the second place, HS271 with 15-150 mg/kg displays robust in vivo anti-inflammatory efficacy as evaluated in rat models of LPS induced TNFα production collagen-induced arthritis. Nonetheless, HS271 exhibits a t1/2 of 3.3 h and Cmax of 2107 ng/mL. Particularly, HS271 is stable in liver microsome assays across other species, including rats, mice, monkeys, and humans. Interestingly, HS271 exhibits oral bioavailability of 67.3%, 58.2%, 14.4%, and 49% in mouse, rat, dog, and monkey, respectively.
All in all, HS271 is a highly potent, orally active, and selective IRAK4 inhibitor.
References:
Wenqiang Zhai, et al. Bioorg Med Chem Lett. 2020 Nov 24;31:127686.