Medical University of South Carolina, College of Pharmacy, Charleston, SC, United States.
Medical University of South Carolina, College of Pharmacy, Charleston, SC, United States.
Adv Cancer Res. 2018;138:183-211. doi: 10.1016/bs.acr.2018.02.006. Epub 2018 Mar 1.
Since the identification and cloning of human histone deacetylases (HDACs) and the rapid approval of vorinostat (Zolinza®) for the treatment of cutaneous T-cell lymphoma, the field of HDAC biology has met many initial successes. However, many challenges remain due to the complexity involved in the lysine posttranslational modifications, epigenetic transcription regulation, and nonepigenetic cellular signaling cascades. In this chapter, we will: review the discovery of the first HDAC inhibitor and present discussion regarding the future of next-generation HDAC inhibitors, give an overview of different classes of HDACs and their differences in lysine deacylation activity, discuss different classes of HDAC inhibitors and their HDAC isozyme preferences, and review HDAC inhibitors' preclinical studies, their clinical trials, their pharmacokinetic challenges, and future direction. We will also discuss the likely reason for the failure of multiple HDAC inhibitor clinical trials in malignancies other than lymphoma and multiple myeloma. In addition, the potential molecular mechanism(s) that may play a key role in the efficacy and therapeutic response rate in the clinic and the likely patient population for HDAC therapy will be discussed.
自人类组蛋白去乙酰化酶（HDACs）的鉴定和克隆以及伏立诺他（Zolinza®）快速获批用于治疗皮肤 T 细胞淋巴瘤以来，HDAC 生物学领域取得了许多初步成功。然而，由于赖氨酸翻译后修饰、表观转录调控和非表观细胞信号级联的复杂性，仍存在许多挑战。在本章中，我们将：回顾第一个 HDAC 抑制剂的发现，并就下一代 HDAC 抑制剂的未来进行讨论，概述不同类别的 HDAC 及其在赖氨酸脱酰基活性方面的差异，讨论不同类别的 HDAC 抑制剂及其对 HDAC 同工酶的偏好，并回顾 HDAC 抑制剂的临床前研究、临床试验、药代动力学挑战和未来方向。我们还将讨论在淋巴瘤和多发性骨髓瘤以外的恶性肿瘤中，多个 HDAC 抑制剂临床试验失败的可能原因。此外，还将讨论可能在临床疗效和治疗反应率中起关键作用的潜在分子机制，以及可能接受 HDAC 治疗的患者人群。
