Structure-Based Drug Design of Novel Indazole/Indolinone-Based Biaryl Derivatives as Oral IRAK4 Inhibitors for the Treatment of Inflammatory Diseases
Zhenwei Zhang, Xue Wang, Xuan Luo, Cong Li, Zesheng Liu, Chunmei Xia, Leyi Yu, Xiaowei Chen, Yaqian Sun, Peipei Wang, Lixin Gao, Xinyue Cao, Yufei Zhang, Yibing Wang, Hong Liu, Yili Sun, Shengbin Zhou, Jia Li, Yu ZhouAbstract
Pathological inflammation in multiple diseases arises from dysregulated innate immune signaling, wherein the interleukin-1 receptor-associated kinase 4 (IRAK4) acts as a critical node that mediates pro-inflammatory cascades and cytokine release downstream of toll-like and interleukin-1 receptors (TLR/IL-1R). Consequently, the therapeutic inhibition of IRAK4 using small molecules has emerged as a promising strategy for these conditions, particularly, rheumatoid arthritis. In this study, we identified a series of novel IRAK4 inhibitors featuring an indazole/indolinone-based biaryl scaffold, and forty-seven novel compounds were designed and synthesized using structure-based rational drug design strategies. Notably, compound 43 exhibited potent molecular and cellular IRAK4 inhibitory activities as well as in vivo anti-inflammatory activities in both LPS-induced acute inflammation and collagen-induced arthritis models alongside favorable pharmacokinetic properties. These findings indicated that compound 43 is a valuable lead compound for further structural optimization and the development of novel IRAK4-targeted anti-inflammatory therapies.