Delving into the Latest Updates on XFL6 with Synapse

Overview

Basic Info

Drug Type

Chemical drugs

Synonyms

XFL0

Target

GCGR x GIPR x GLP-1R

Mechanism

GCGR agonists(Glucagon receptor agonists), GIPR agonists(Gastric inhibitory polypeptide receptor agonists), GLP-1R agonists(Glucagon-like peptide 1 receptor agonists)

Therapeutic Areas

Endocrinology and Metabolic Disease

Active Indication

Diabetes MellitusObesity

Inactive Indication-

Originator Organization

First Affiliated Hospital of Xi'an Jiaotong University

Active Organization

First Affiliated Hospital of Xi'an Jiaotong University

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

AIMSTo design and screen a potent GLP-1/GIP/Gcg receptors triagonist with therapeutic potential in rodent animals with diabetes and obesity.MAIN METHODSFirst, we obtained a 12-mer dual GIP/Gcg receptor agonist from a large combinatorial peptide library via high-throughput screening technique and then fused to the Exendin (9-39) to generate a potent GLP-1/GIP/Gcg triagonist. Further site fatty chain modification was performed to improve the druggability via enhancing in vivo stability and cyclic half-life. In vitro signaling and functional assays in cell lines expressing each receptor and in vivo efficacy evaluation in rodent model animals with hyperglycemia and obesity were all carefully performed.KEY FINDINGSWe screened and obtained a potent GLP-1/GIP/Gcg triagonist, termed XFL0, which promotes in vitro GLP-1, GIP, Gcg receptor activation comparable to native GLP-1, GIP and glucagon, respectively. Site-specific fatty acid modification significantly enhanced plasma stability of XFL0 and exhibited no obvious impact on receptor activation. The selected XFL0 conjugates termed XFL6, showed glucose-dependent insulin secretion and improved glucose tolerance by acting on all GLP-1, GIP and Gcg receptors in gene-deficient mice of which the effects were all significantly greater than any single receptor agonist. After chronic treatment in rodent animals with diabetes and obesity, XFL6 potently decreased body weight and food intake, ameliorated the hyperglycemia and hemoglobin A1c levels as well as the lipid metabolism and diabetic nephropathy related disorders.SIGNIFICANCEXFL6, as a novel GLP-1/GIP/Gcg receptor triagonist, held potential to deliver outstanding improvement in correcting hyperglycemia, obesity and diabetic nephropathy.

100 Deals associated with XFL6

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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	First Affiliated Hospital of Xi'an Jiaotong University	01 Nov 2020
Obesity	Preclinical	CN	First Affiliated Hospital of Xi'an Jiaotong University	01 Nov 2020