College of Pharmacy, Jinan University, Guangzhou, 510632, China.
Integrated Chinese and Western Medicine Postdoctoral research station, Jinan University, Guangzhou, 510632, China.
Theranostics. 2020 Mar 4;10(9):4168-4182. doi: 10.7150/thno.43834. eCollection 2020.
REV-ERBα (NR1D1) is a circadian clock component that functions as a transcriptional repressor. Due to its role in direct modulation of metabolic genes, REV-ERBα is regarded as an integrator of cell metabolism with circadian clock. Accordingly, REV-ERBα is first proposed as a drug target for treating sleep disorders and metabolic syndromes (e.g., dyslipidaemia, hyperglycaemia and obesity). Recent years of studies uncover a rather broad role of REV-ERBα in pathological conditions including local inflammatory diseases, heart failure and cancers. Moreover, REV-ERBα is involved in regulation of circadian drug metabolism that has implications in chronopharmacology. In the meantime, recent years have witnessed discovery of an array of new REV-ERBα ligands most of which have pharmacological activities . In this article, we review the regulatory role of REV-ERBα in various types of diseases and discuss the underlying mechanisms. We also describe the newly discovered ligands and the old ones together with their targeting potential. Despite well-established pharmacological effects of REV-ERBα ligands in animals (preclinical studies), no progress has been made regarding their translation to clinical trials. This implies certain challenges associated with drug development of REV-ERBα ligands. In particular, we discuss the potential challenges related to drug safety (or adverse effects) and bioavailability. For new drug development, it is advocated that REV-ERBα should be targeted to treat local diseases and a targeting drug should be locally distributed, avoiding the adverse effects on other tissues.
REV-ERBα（NR1D1）是昼夜节律钟的组成部分，作为转录抑制剂发挥作用。由于其在直接调节代谢基因方面的作用，REV-ERBα被认为是细胞代谢与昼夜节律的整合因子。因此，REV-ERBα最初被提议作为治疗睡眠障碍和代谢综合征（如血脂异常、高血糖和肥胖症）的药物靶点。近年来的研究揭示了 REV-ERBα在局部炎症性疾病、心力衰竭和癌症等病理状态下的广泛作用。此外，REV-ERBα还参与昼夜节律药物代谢的调节，这对时间药理学有影响。与此同时，近年来发现了一系列新的 REV-ERBα配体，其中大多数具有药理学活性。本文综述了 REV-ERBα在各种疾病中的调节作用，并讨论了其潜在的机制。我们还描述了新发现的配体和旧的配体及其靶向潜力。尽管 REV-ERBα配体在动物（临床前研究）中具有明确的药理学作用，但在将其转化为临床试验方面没有取得进展。这意味着与 REV-ERBα配体的药物开发相关的某些挑战。特别是，我们讨论了与药物安全性（或不良反应）和生物利用度相关的潜在挑战。对于新药开发，建议将 REV-ERBα作为治疗局部疾病的靶点，并局部分布靶向药物，避免对其他组织产生不良反应。
