IRAK-4 inhibitor(Baltimore VA Medical Center)

The interleukin-1 receptor associated kinase 4 (IRAK-4) is a member of serine-threonine kinase family, which plays an important role in the regulation of interleukin-1 receptors (IL-1R) and Toll-like receptors (TLRs) related signaling pathways. At present, the IRAK-4 mediated inflammation and related signaling pathways contribute to inflammation, which are also responsible for other autoimmune diseases and drug resistance in cancers. Therefore, targeting IRAK-4 to develop single-target, multi-target inhibitors and proteolysis-targeting chimera (PROTAC) degraders is an important direction for the treatment of inflammation and related diseases. Moreover, insight into the mechanism of action and structural optimization of the reported IRAK-4 inhibitors will provide the new direction to enrich the clinical therapies for inflammation and related diseases. In this comprehensive review, we introduced the recent advance of IRAK-4 inhibitors and degraders with regards to structural optimization, mechanism of action and clinical application that would be helpful for the development of more potent chemical entities against IRAK-4.

Interleukin‐1 Receptor‐Associated Kinase 4 (IRAK‐4) has crucial functions in inflammation, innate immunity, and malignancy. Structure‐based pharmacophore modeling integrated with validated QSAR analysis was implemented to discover structurally novel IRAK‐4 inhibitors from natural products database. The QSAR model combined molecular descriptors with structure‐based pharmacophore capable of explaining bioactivity variation of structurally diverse IRAK‐4 inhibitors. Manually built pharmacophore model, validated with receiver operating characteristic curve, and selected using the statistically optimum QSAR equation, was applied as a 3D‐search query to mine AnalytiCon Discovery database of natural products. Experimental in vitro testing of highest‐ranked hits identified uvaretin, saucerneol, and salvianolic acid B as active IRAK‐4 inhibitors with IC50 values in low micromolar range.