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Identification of an Anti-diabetic, Orally Available Small Molecule that Regulates TXNIP Expression and Glucagon Action.
Cell Metabolism ( IF 27.7 ) Pub Date : 2020-07-28 , DOI: 10.1016/j.cmet.2020.07.002
Lance A Thielen 1 , Junqin Chen 1 , Gu Jing 1 , Omar Moukha-Chafiq 2 , Guanlan Xu 1 , SeongHo Jo 1 , Truman B Grayson 1 , Brian Lu 1 , Peng Li 3 , Corinne E Augelli-Szafran 2 , Mark J Suto 2 , Matt Kanke 4 , Praveen Sethupathy 4 , Jason K Kim 5 , Anath Shalev 1
Affiliation  

Diabetes is characterized by hyperglycemia, loss of functional islet beta cell mass, deficiency of glucose-lowering insulin, and persistent alpha cell secretion of gluconeogenic glucagon. Still, no therapies that target these underlying processes are available. We therefore performed high-throughput screening of 300,000 compounds and extensive medicinal chemistry optimization and here report the discovery of SRI-37330, an orally bioavailable, non-toxic small molecule, which effectively rescued mice from streptozotocin- and obesity-induced (db/db) diabetes. Interestingly, in rat cells and in mouse and human islets, SRI-37330 inhibited expression and signaling of thioredoxin-interacting protein, which we have previously found to be elevated in diabetes and to have detrimental effects on islet function. In addition, SRI-37330 treatment inhibited glucagon secretion and function, reduced hepatic glucose production, and reversed hepatic steatosis. Thus, these studies describe a newly designed chemical compound that, compared to currently available therapies, may provide a distinct and effective approach to treating diabetes.



中文翻译:

鉴定调节 TXNIP 表达和胰高血糖素作用的抗糖尿病、口服小分子。

糖尿病的特征是高血糖、功能性胰岛β细胞团的丧失、降糖胰岛素的缺乏和糖异生胰高血糖素的持续α细胞分泌。尽管如此,还没有针对这些潜在过程的疗法可用。因此,我们对 300,000 种化合物进行了高通量筛选和广泛的药物化学优化,并在此报告了 SRI-37330 的发现,这是一种口服生物可利用的无毒小分子,可有效地将小鼠从链脲佐菌素和肥胖诱导 ( db / db) 糖尿病。有趣的是,在大鼠细胞以及小鼠和人类胰岛中,SRI-37330 抑制了硫氧还蛋白相互作用蛋白的表达和信号传导,我们之前发现该蛋白在糖尿病中升高并对胰岛功能产生不利影响。此外,SRI-37330 治疗抑制了胰高血糖素的分泌和功能,减少了肝葡萄糖的产生,并逆转了肝脂肪变性。因此,这些研究描述了一种新设计的化合物,与目前可用的疗法相比,它可以提供一种独特而有效的治疗糖尿病的方法。

更新日期:2020-09-01
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