European Institute of Oncology, Drug Discovery Unit, Department of Experimental Oncology, Via Celoria 26, 20133 Milan, Italy.
Expert Opin Drug Discov. 2011 Apr;6(4):393-404. doi: 10.1517/17460441.2011.557660. Epub 2011 Feb 23.
HDAC inhibitors have demonstrated potent anticancer activities in preclinical and clinical studies. Currently, two drugs (SAHA and romidepsin) have gained the FDA approval for the treatment of cutaneous T-cell lymphoma. Clinical efficacy of HDAC inhibitors has been observed in advanced hematological malignancies, while response in other cancers has been in most cases unpredictable and often rather limited. The search for new molecules with the potential to overcome the limitations of the first HDAC inhibitors has become a primary goal in the field of epigenetic drug discovery as well as drugs acting on other chromatin modifying enzymes.
The article shortlists seven new HDAC inhibitors that have recently entered clinical studies as representative examples of next generation drugs. The most recently published preclinical profile is reviewed, together with the first clinical data for these compounds. The article then focuses on challenges faced during the progress of first generation HDAC inhibitors and analyzes whether these new compounds are likely to provide a solution to the existing issues and needs.
Next generation HDAC inhibitors have the 'best-in-class' potential, particularly regarding potency and in vivo exposure. However, several issues remain unresolved. For example, none of the presented compounds appears to have a significantly different selectivity profile towards various HDAC isoforms and, thus, none of them may provide a further elucidation between the toxicity seen in more advanced HDAC inhibitors and isoform selectivity. Additionally, a need for a continuous effort on target validation is seen as a necessary requirement for further progress in the field.
组蛋白去乙酰化酶（HDAC）抑制剂在临床前和临床研究中表现出强大的抗癌活性。目前，两种药物（SAHA 和罗米地辛）已获得美国食品药品监督管理局（FDA）批准，用于治疗皮肤 T 细胞淋巴瘤。HDAC 抑制剂的临床疗效已在晚期血液恶性肿瘤中观察到，而在其他癌症中的反应在大多数情况下是不可预测的，且往往相当有限。寻找具有克服第一代 HDAC 抑制剂局限性潜力的新分子，已成为表观遗传学药物发现领域以及作用于其他染色质修饰酶的药物的主要目标。
本文精选了七种最近进入临床研究的新型 HDAC 抑制剂，作为下一代药物的代表。本文回顾了这些化合物的最新发表的临床前概况，并结合了这些化合物的首批临床数据。然后，本文重点讨论了第一代 HDAC 抑制剂进展中面临的挑战，并分析了这些新型化合物是否有可能解决现有问题和需求。
下一代 HDAC 抑制剂具有“同类最佳”的潜力，尤其是在效力和体内暴露方面。然而，仍有几个问题尚未解决。例如，所呈现的化合物似乎没有针对各种 HDAC 同工酶的明显不同的选择性谱，因此，它们都无法在更先进的 HDAC 抑制剂的毒性和同工酶选择性之间提供进一步的解释。此外，还需要不断努力验证靶点，这被视为该领域进一步发展的必要条件。
