Delving into the Latest Updates on NOX-6-18 with Synapse

Overview

Basic Info

Drug Type

Chemical drugs

Synonyms

NOX6-18

Target

GPR132

Mechanism

GPR132 antagonists(G protein-coupled receptor 132 antagonists)

Therapeutic Areas

Endocrinology and Metabolic Disease

Active Indication

Diabetes Mellitus

Inactive Indication-

Originator Organization

Peking University

Active Organization

Shandong UniversityInstitute of Biophysics of Chinese Academy of Sciences

Peking University

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Author: Dou, Xiao-Dong ; Sha, Xue-Ying ; Zhao, Xin-Yi ; Wang, Jia-Le ; Huo, Tong-Yu ; Li, Yu ; Zhang, Wen-Hui ; Liu, Ya-Meng ; Yu, Xiao ; Zhang, Cheng ; Ding, Wei ; Jiao, Ning ; Hao, Yong ; Zhang, Cai-Fang ; Cheng, Jie ; Wang, Si-Han ; Sun, Jin-Peng ; Gao, Ming-Xin ; Xu, Guo-Feng ; Ding, Jin-Hui ; Ji, Zhao-Wei ; Gao, Jia-Rui

Chronic inflammation due to islet-residing macrophages plays key roles in the development of type 2 diabetes mellitus. By systematically profiling intra-islet lipid-transmembrane receptor signalling in islet-resident macrophages, we identified endogenous 9(S)-hydroxy-10,12-octadecadienoic acid-G-protein-coupled receptor 132 (GPR132)-Gi signalling as a significant contributor to islet macrophage reprogramming and found that GPR132 deficiency in macrophages reversed metabolic disorders in mice fed a high-fat diet. The cryo-electron microscopy structures of GPR132 bound with two endogenous agonists, N-palmitoylglycine and 9(S)-hydroxy-10,12-octadecadienoic acid, enabled us to rationally design both GPR132 agonists and antagonists with high potency and selectivity through stepwise translational approaches. We ultimately identified a selective GPR132 antagonist, NOX-6-18, that modulates macrophage reprogramming within pancreatic islets, decreases weight gain and enhances glucose metabolism in mice fed a high-fat diet. Our study not only illustrates that intra-islet lipid signalling contributes to islet macrophage reprogramming but also provides a broadly applicable strategy for the identification of important G-protein-coupled receptor targets in pathophysiological processes, followed by the rational design of therapeutic leads for refractory diseases such as diabetes.

100 Deals associated with NOX-6-18

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetes Mellitus	Preclinical	CN	Institute of Biophysics of Chinese Academy of Sciences	28 Sep 2023
Diabetes Mellitus	Preclinical	CN	Peking University	28 Sep 2023
Diabetes Mellitus	Preclinical	CN	Shandong University	28 Sep 2023