Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
Cell Mol Life Sci. 2021 Jan;78(1):207-225. doi: 10.1007/s00018-020-03490-2. Epub 2020 Mar 5.
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.
NAD(P)-依赖性固醇脱氢酶样（NSDHL）是人类胆固醇合成中的一种必需酶，也是表皮生长因子受体（EGFR）运输途径的调节剂，由于其与胆固醇相关疾病和癌的密切相关性，它已成为治疗靶点的研究热点。然而，由于缺乏 NSDHL 的原子细节，针对 NSDHL 的药物开发受到了阻碍。在这项研究中，我们报告了两种人类 NSDHL 的 X 射线晶体结构，揭示了辅酶结合位点的详细描述以及结合辅酶时独特的构象变化。进行了基于结构的虚拟筛选和生化评估，并鉴定出一种新型的 NSDHL 抑制剂，该抑制剂对 EGFR 具有抑制活性。在 EGFR 驱动的人类癌细胞中，用有效的 NSDHL 抑制剂处理可增强 EGFR 激酶抑制剂的抗肿瘤作用。总的来说，这些发现可以为开发针对 NSDHL 相关疾病的治疗剂提供良好的平台。
