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.
Zhenwei Zhang, Xue Wang, Xuan Luo et al.· Journal of Medicinal Chemist...· 0 citations
Hydrogen sulfide (H2S) is an endogenous gasotransmitter with therapeutic potential for stroke. Our previous work identified that ADT-OH, an H2S donor with mitochondrial uncoupling activity, protects against stroke by activating the SQR-UCP2-AMPK pathway. Here, we launched a medicinal chemistry campaign based on hit compound ADT-OH to design and synthesize 30 novel derivatives, among which compound 16 displayed more potent mitochondrial uncoupling activity than ADT-OH, effectively reducing the mitochondrial membrane potential at a low concentration of 1 μM. In mouse models of ischemic and hemorrhagic stroke, compound 16 significantly alleviated brain injury and improved functional outcomes. Notably, these therapeutic effects were completely abolished in microglia/macrophage-specific SQR deletion (Cx3cr1Cre: Sqrfl/fl) mice, confirming that the biological function of compound 16 is mediated by a strictly SQR-dependent mechanism. Proteomic analysis further validated these findings. Overall, compound 16 represents a promising lead compound for stroke therapy based on a novel mechanism, warranting further development.
Peng Song, Yuan Li, Xiaohan Song et al.· Journal of Medicinal Chemist...· 0 citations
Leucine-rich pentatricopeptide repeat containing (LRPPRC), a critical regulator of mitochondrial gene expression, is overexpressed in various malignancies and sustains oxidative phosphorylation (OXPHOS)-dependent adenosine triphosphate (ATP) production essential for tumor growth, chemoresistance, and stem cell survival, rendering it a promising therapeutic target. Herein, using an aptamer-assisted fluorescence polarization platform, we identified acylhydrazone-skeleton inhibitors targeting LRPPRC's RNA-binding domain, leading to the design and synthesis of over 60 derivatives. Lead compound 3o exhibited excellent LRPPRC inhibitory activity (92% at 6.25 μM vs 38% for gossypol acetate (GAA)) and induced robust LRPPRC degradation. Notably, 3o downregulated downstream OXPHOS subunits and ATP synthase, eliciting broad antiproliferative effects, particularly in refractory and drug-resistant A549, BXPC-3, and NCI-H1975 cells (IC50 = 0.54, 0.27, and 1.39 μM, respectively). In PC9 and HCT116 xenografts, 3o achieved tumor growth inhibition (TGI) rates of 73 and 49% with favorable safety profiles. Overall, we developed novel biphenyl-acylhydrazone LRPPRC inhibitors as potent antitumor agents acting via OXPHOS modulation, providing a valuable lead compound for cancer therapy.
Hairu Ren, Jie Liu, Dachi Wang et al.· Journal of Medicinal Chemist...· 0 citations
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