Glucolipotoxicity (GLT), in which elevated levels of glucose and fatty acids have deleterious effects on β-cell biology, is thought to be one of the major contributors in progression of type 2 diabetes. In search of novel small molecules that protects β-cells against GLT, we previously discovered KD025, an inhibitor of Rho-associated coiled-coil containing kinase isoform 2 (ROCK2), as a GLT-protective compound in INS-1E cells and dissociated human islets. To further understand the mechanism of action of KD025, we found that pharmacological and genetic inhibition of ROCK2 was not responsible for the protective effects of KD025 against GLT. Instead, kinase profiling revealed that KD025 potently inhibits catalytic subunits of casein kinase 2 (CK2), a constitutively active serine/threonine kinase. We experimentally verified that the inhibition of one of the catalytic subunits of casein kinase 2, CK2A1, but not CK2A2, improved cell viability when challenged with GLT. We conclude that KD025 inhibits CK2 to protect β-cells from glucolipotoxicity.

中文翻译：

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KD025 是一种酪蛋白激酶 2 抑制剂，可防止 β 细胞发生糖脂毒性

糖脂毒性 (GLT) 是指葡萄糖和脂肪酸水平升高对 β 细胞生物学产生有害影响，被认为是 2 型糖尿病进展的主要因素之一。在寻找保护 β 细胞免受 GLT 侵害的新型小分子时，我们之前发现了 KD025，一种含有激酶亚型 2 (ROCK2) 的 Rho 相关卷曲螺旋抑制剂，可作为 INS-1E 细胞和​​解离人细胞中的 GLT 保护化合物。胰岛。为了进一步了解 KD025 的作用机制，我们发现 ROCK2 的药理学和遗传抑制并不是 KD025 对 GLT 的保护作用的原因。相反，激酶分析显示 KD025 有效抑制酪蛋白激酶 2 (CK2) 的催化亚基，酪蛋白激酶 2 是一种组成型活性丝氨酸/苏氨酸激酶。我们通过实验证实，抑制酪蛋白激酶 2 的催化亚基之一 CK2A1（而非 CK2A2）可提高 GLT 攻击时的细胞活力。我们得出结论，KD025 抑制 CK2 以保护 β 细胞免受糖脂毒性。