Discovery of LY3325656: A GPR142 agonist suitable for clinical testing in human

Liu, Lian Zhu; Li, Zhenning; Zhou, Jia; Hu, Zhi Long; Zhang, Xue Jun; Zhang, Hai Zhen; Mi, Zeng; Liu, Jia; Li, Lei; Jiang, Yi; Zou, Zack; Wang, Fan; Zhang, Lei; Xu, Jianfeng; Wang, Jingru; Xiao, Fei; Fang, Xiankang; Zou, Haixia; Efanov, Alexander M.; Thomas, Melissa K.; Lin, Hua; Chen, Jiehao

doi:10.1016/j.bmcl.2019.126857

Cited by 7 publications

(3 citation statements)

References 21 publications

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“…One of these has reached phase 1 in clinical trials for type 2 diabetes treatment (Fig. 1D) [139]. Moreover, GPR142, along with CasR, GPR35 and TAAR1, act as sensors of dietary amino acids and gut microbiota amino acid metabolites and control hormone secretion in enteroendocrine cells.…”

Section: Gpcrs Sense Amino Acids and Amino Acid‐derived Metabolitesmentioning

confidence: 99%

Nutritional and metabolic signalling through GPCRs

et al. 2022

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Deregulated metabolism is a well-known feature of several challenging diseases, including diabetes, obesity and cancer. Besides their important role as intracellular bioenergetic molecules, dietary nutrients and metabolic intermediates are released in the extracellular environment. As such, they may achieve unconventional roles as hormone-like molecules by activating cell surface G-protein-coupled receptors (GPCRs) that regulate several pathophysiological processes. In this review, we provide an insight into the role of lactate, succinate, fatty acids, amino acids as well as ketogenesis-derived and b-oxidation-derived intermediates as extracellular signalling molecules. Moreover, the mechanisms by which their cognate metabolite-sensing GPCRs integrate nutritional and metabolic signals with specific intracellular pathways will be described. A better comprehension of these aspects is of fundamental importance to identify GPCRs as novel druggable targets.

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Section: Gpcrs Sense Amino Acids and Amino Acid‐derived Metabolitesmentioning

confidence: 99%

Nutritional and metabolic signalling through GPCRs

et al. 2022

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“…In addition, GPR142 agonists also increased β-cell proliferation, which they interpreted to be an indirect effect mediated through local production of GLP-1 in the islets. Thus, GPR142 agonists could potentially modify metabolism through a balanced action of gut hormones as both insulin and glucagon and is a novel therapeutic approach for treating diabetes with minimal risk for hypoglycemia which has led to the design of synthetic GPR142 agonists, which have recently reached phase 1 in clinical trials for Type 2 diabetes treatment [ 372 , 373 ].…”

Section: Amino Acid Metabolitesmentioning

confidence: 99%

Metabolite G-Protein Coupled Receptors in Cardio-Metabolic Diseases

Strassheim

Sullivan

Irwin

et al. 2021

Cells

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G protein-coupled receptors (GPCRs) have originally been described as a family of receptors activated by hormones, neurotransmitters, and other mediators. However, in recent years GPCRs have shown to bind endogenous metabolites, which serve functions other than as signaling mediators. These receptors respond to fatty acids, mono- and disaccharides, amino acids, or various intermediates and products of metabolism, including ketone bodies, lactate, succinate, or bile acids. Given that many of these metabolic processes are dysregulated under pathological conditions, including diabetes, dyslipidemia, and obesity, receptors of endogenous metabolites have also been recognized as potential drug targets to prevent and/or treat metabolic and cardiovascular diseases. This review describes G protein-coupled receptors activated by endogenous metabolites and summarizes their physiological, pathophysiological, and potential pharmacological roles.

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“…Since L-Trp stimulates insulin secretion and improves glucose tolerance, GPR142 was rapidly associated to a potential role in the regulation of glucose homeostasis and in metabolic diseases such as obesity or diabetes [129]. This has motivated the design of synthetic GPR142 agonists, one of this has recently reached phase 1 in clinical trials for Type 2 diabetes treatment [130].…”

Section: G-protein-coupled Receptor 142 (Gpr142)mentioning

confidence: 99%

Metabolite Sensing GPCRs: Promising Therapeutic Targets for Cancer Treatment?

Cosín-Roger

Ortiz-Masiá

Barrachina

et al. 2020

Cells

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G-protein-coupled receptors constitute the most diverse and largest receptor family in the human genome, with approximately 800 different members identified. Given the well-known metabolic alterations in cancer development, we will focus specifically in the 19 G-protein-coupled receptors (GPCRs), which can be selectively activated by metabolites. These metabolite sensing GPCRs control crucial processes, such as cell proliferation, differentiation, migration, and survival after their activation. In the present review, we will describe the main functions of these metabolite sensing GPCRs and shed light on the benefits of their potential use as possible pharmacological targets for cancer treatment.

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Discovery of LY3325656: A GPR142 agonist suitable for clinical testing in human

Cited by 7 publications

References 21 publications

Nutritional and metabolic signalling through GPCRs

Nutritional and metabolic signalling through GPCRs

Metabolite G-Protein Coupled Receptors in Cardio-Metabolic Diseases

Metabolite Sensing GPCRs: Promising Therapeutic Targets for Cancer Treatment?

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