The glucagon-like peptide-1 receptor (GLP-1R) is one of the preeminent class B G-protein coupled receptor(GPCRs) as both its physiologic control of insulin secretion, and its ligand binding-receptor interactions using structural biology[1]. BETP represents a novel small-molecule activator of GLP-1R, and exhibits glucose-dependent insulin secretion in rats following i.v. (but not oral) administration[2]. Sustained degradation of BETP with small-molecule BET proteolysis-targeting chimera (PROTAC), ARV-825, resulted in marked downregulation of surface CXCR4 and CD44, key proteins in leukemia-microenvironment interaction, in AML cells. BETP degradation markedly decreased CD34+CD38-CD90-CD45RA+ leukemic stem cell population and alone or in combination with Cytarabine, prolonged survival in mouse model of human leukemia including AML-PDX[3]. BETP increases the potency of oxyntomodulin by 10-fold (EC50 of 80 pM). GLP-1 does not change the potencies and efficacies of both oxyntomodulin and glucagon at the glucagon receptor. BETP (0-30 μM) increases the binding affinity of oxyntomodulin for the GLP-1 receptor. BETP (5 mg/kg) enhances oxyntomodulin-stimulated insulin secretion[4]. BETP has insulinotropic effect in SD rats. BETP (10 mg/kg, jugular vein cannula) exhibits insulin secretagogue activity in the intravenous glucose tolerance test (IVGTT) model. BETP (10 mg/kg, i.v.)-treated rats need 20% higher glucose infusion rates and demonstrates higher plasma insulin levels in SD rat hyperglycemic clamp model[5].
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