Bieliauskas Anton V, Weerasinghe Sujith V W, Negmeldin Ahmed T, Pflum Mary Kay H
Department of Chemistry, Wayne State University, Detroit, MI, USA.
Arch Pharm (Weinheim). 2016 May;349(5):373-82. doi: 10.1002/ardp.201500472. Epub 2016 Apr 9.
Histone deacetylase (HDAC) proteins have emerged as targets for anti-cancer therapeutics, with several inhibitors used in the clinic, including suberoylanilide hydroxamic acid (SAHA, vorinostat). Because SAHA and many other inhibitors target all or most of the 11 human HDAC proteins, the creation of selective inhibitors has been studied intensely. Recently, inhibitors selective for HDAC1 and HDAC2 were reported where selectivity was attributed to interactions between substituents on the metal binding moiety of the inhibitor and residues in the 14-Å internal cavity of the HDAC enzyme structure. Based on this earlier work, we synthesized and tested SAHA analogs with substituents on the hydroxamic acid metal binding moiety. The N-substituted SAHA analogs displayed reduced potency and solubility, but greater selectivity, compared to SAHA. Docking studies suggested that the N-substituent accesses the 14-Å internal cavity to impart preferential inhibition of HDAC1. These studies with N-substituted SAHA analogs are consistent with the strategy exploiting the 14-Å internal cavity of HDAC proteins to create HDAC1/2 selective inhibitors.
组蛋白去乙酰化酶（HDAC）蛋白已成为抗癌治疗的靶点，临床上使用了多种抑制剂，包括辛二酰苯胺异羟肟酸（SAHA，伏立诺他）。由于SAHA和许多其他抑制剂靶向所有或大多数11种人类HDAC蛋白，因此对选择性抑制剂的研发进行了深入研究。最近，有报道称对HDAC1和HDAC2具有选择性的抑制剂，其选择性归因于抑制剂金属结合部分上的取代基与HDAC酶结构14埃内腔中的残基之间的相互作用。基于早期的这项工作，我们合成并测试了在异羟肟酸金属结合部分带有取代基的SAHA类似物。与SAHA相比，N-取代的SAHA类似物效力和溶解度降低，但选择性更高。对接研究表明，N-取代基进入14埃内腔以优先抑制HDAC1。这些对N-取代SAHA类似物的研究与利用HDAC蛋白的14埃内腔来创建HDAC1/2选择性抑制剂的策略是一致的。
