Abstract

NAD(P)-dependent steroid dehydrogenase-like (NSDHL), an essential enzyme in human cholesterol synthesis and a regulator of epidermal growth factor receptor (EGFR) trafficking pathways, has attracted interest as a therapeutic target due to its crucial relevance to cholesterol-related diseases and carcinomas. However, the development of pharmacological agents for targeting NSDHL has been hindered by the absence of the atomic details of NSDHL. In this study, we reported two X-ray crystal structures of human NSDHL, which revealed a detailed description of the coenzyme-binding site and the unique conformational change upon the binding of a coenzyme. A structure-based virtual screening and biochemical evaluation were performed and identified a novel inhibitor for NSDHL harboring suppressive activity towards EGFR. In EGFR-driven human cancer cells, treatment with the potent NSDHL inhibitor enhanced the antitumor effect of an EGFR kinase inhibitor. Overall, these findings could serve as good platforms for the development of therapeutic agents against NSDHL-related diseases.

中文翻译：

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人 NSDHL 的晶体结构及其具有抑制 EGFR 活性潜力的新型抑制剂的开发

 抽象的

NAD(P) 依赖性类固醇脱氢酶样 (NSDHL) 是人类胆固醇合成中的必需酶，也是表皮生长因子受体 (EGFR) 运输途径的调节剂，由于其与胆固醇的重要相关性，作为治疗靶点引起了人们的兴趣。相关疾病和癌症。然而，由于缺乏 NSDHL 的原子细节，靶向 NSDHL 的药物的开发受到阻碍。在这项研究中，我们报道了人类 NSDHL 的两种 X 射线晶体结构，揭示了辅酶结合位点的详细描述以及辅酶结合时独特的构象变化。进行了基于结构的虚拟筛选和生化评估，并鉴定了一种对 EGFR 具有抑制活性的 NSDHL 新型抑制剂。在 EGFR 驱动的人类癌细胞中，使用强效 NSDHL 抑制剂治疗可增强 EGFR 激酶抑制剂的抗肿瘤作用。总的来说，这些发现可以作为开发针对 NSDHL 相关疾病的治疗药物的良好平台。