Phosphatidylinositol 3-kinase Class IIγ (PI3KC2γ) is a critical regulator of PI(3,4)P₂ production on endosomal membranes, linking its activity to metabolic disorders such as diabetes, glycogen storage diseases, and hyperlipidemia. Despite its importance, selective inhibitors targeting PI3KC2γ remain underexplored. In this study, we developed novel scaffolds for PI3KC2γ inhibitors using structure-based design. A series of inhibitors were synthesized, among which compound 23 was identified as the most potent PI3KC2γ inhibitor reported to date. Functional assays confirmed that compound 23 effectively inhibits insulin-stimulated PI(3,4)P₂ formation, blocks glucose-to-glycogen conversion, and reduces excessive liver glycogen accumulation by downregulating the Akt2-glycogen synthase pathway. This study highlights the therapeutic potential of PI3KC2γ inhibition in glycogen storage diseases and provides efficient tool molecules for further drug development.

01 Feb 2025·European Journal of Medicinal Chemistry

Discovery of novel biaryl urea derivatives against IL-1β release with low toxicity based on NEK7 inhibitor

Article

Author: Hu, Youhong ; Wang, Haoyu ; Jia, Yulei ; Zhu, Kehan ; Tang, Wei ; Tian, Ziyang ; Wang, Leibo ; Feng, Chunlan ; Qi, Luyao

Aberrant activation of NLRP3 inflammasome is involved in various inflammatory diseases, making it a promising target for therapeutic intervention. NEK7, a member of the NIMA-related kinase (NEK) family, functions as a key NLRP3-binding protein and plays a crucial role in the regulation of NLRP3 inflammasome assembly and activation. Thus, disrupting NLRP3-NEK7 interactions by targeting NEK7 could be a promising strategy to inhibit the activation of NLRP3 inflammasome. In this work, a series of novel urea derivatives were designed and synthesized based on the reported NEK7 inhibitors. Among these, compound 23 exhibited potent activity against IL-1β release with low cytotoxicity. Moreover, compound 23 enhanced the thermal stability of NEK7 and disrupted the NLRP3-NEK7 interaction, thereby regulating NLRP3 inflammasome assembly.

01 Dec 2024·European Journal of Medicinal Chemistry

Scaffold hopping-driven optimization for the identification of NLRP3 inhibitors as potential gout therapeutics

Article

Author: Zhang, Xiangyu ; Yu, Jie. ; Zhang, Liangren. ; Liu, Zhenming ; Shi, Cheng ; Lyu, Weiping. ; Yu, Jie ; Chen, Yanming. ; Liu, Zhenming. ; Zhang, Xiangyu. ; Shi, Cheng. ; Xiu, Siyu ; Chen, Yanming ; Xiu, Siyu. ; Zhang, Liangren ; Lyu, Weiping

Gout as a common inflammatory arthritis seriously affects the quality of life of a large number of people. Targeting NLRP3 inflammasome has been certified as a promising therapeutic strategy for gout. This study, a series of new imidazolidinone derivatives were validated as NLRP3 inhibitors by scaffold hopping from the reported NLRP3 inhibitor CSC-6. In contrast to the poor physicochemical properties of the template molecule, the representative compound 23 showed good plasma stability, water solubility, and no significant inhibitory toxicity to CYP450 enzymes. Surface plasmon resonance and immunoblotting experiments showed that compound 23 binds NLRP3 and inhibits NLRP3 activation. Finally, compound 23 showed good anti-inflammatory and analgesic effects in acute peritonitis and arthritis. Overall, the present study provides NLRP3 inhibitors with favorable pharmacological properties, which may not only serve as a tool molecule for studying NLRP3-related functions, but also may further facilitate the gout treatment.

100 Deals associated with Galactose-based diruthenium conjugate(University of Bern)

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Indication	Highest Phase	Country/Location	Organization	Date
Toxoplasmosis	Preclinical	Switzerland	University of Bern	16 Jan 2023

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