Department of Chemistry, The Scripps Research Institute, La Jolla, California, 92037, USA.
Sci Data. 2023 Oct 4;10(1):676. doi: 10.1038/s41597-023-02596-z.
A central regulator of metabolism, transcription factor carbohydrate response element binding protein (ChREBP) senses and responds to dietary glucose levels by stimulating the transcription of glycolytic and lipogenic enzymes. Genetic depletion of ChREBP rescues β-cell dysfunction arising from high glucose levels, suggesting that inhibiting ChREBP might represent an attractive therapeutic approach to manage diabetes and other metabolic diseases. However, the molecular mechanisms governing ChREBP activation are poorly understood and chemical tools to probe the cellular activity of ChREBP are lacking. Here, we report a high-throughput pharmacological screen in INS-1E β-cells that identified novel inhibitors of ChREBP-driven transcription at carbohydrate response element sites, including three putative covalent inhibitors and two likely non-covalent chemical scaffolds. This work affords a pharmacological toolkit to help uncover the signaling logic controlling ChREBP activation and may ultimately reveal potential therapeutic approaches for treating metabolic disease.
代谢的中央调节因子，转录因子碳水化合物反应元件结合蛋白（ChREBP）通过刺激糖酵解和脂肪生成酶的转录来感知和响应膳食葡萄糖水平。ChREBP 的基因耗竭可挽救高葡萄糖水平引起的β细胞功能障碍，这表明抑制 ChREBP 可能是治疗糖尿病和其他代谢疾病的一种有吸引力的治疗方法。然而，调节 ChREBP 激活的分子机制知之甚少，缺乏用于探测 ChREBP 细胞活性的化学工具。在这里，我们在 INS-1E β 细胞中进行了高通量药理学筛选，鉴定了碳水化合物反应元件位点上 ChREBP 驱动转录的新型抑制剂，包括三种可能的共价抑制剂和两种可能的非共价化学支架。这项工作提供了一个药理学工具包，有助于揭示控制 ChREBP 激活的信号逻辑，并可能最终为治疗代谢疾病提供潜在的治疗方法。
