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.

中文翻译：

---

组蛋白脱乙酰酶抑制剂的结构要求：异羟肟酸修饰的 SAHA 类似物

组蛋白去乙酰化酶 (HDAC) 蛋白已成为抗癌治疗的靶点，临床上使用了几种抑制剂，包括辛二酰苯胺异羟肟酸（SAHA、伏立诺他）。由于 SAHA 和许多其他抑制剂针对 11 种人类 HDAC 蛋白中的全部或大部分，因此对选择性抑制剂的产生进行了深入研究。最近，报道了对 HDAC1 和 HDAC2 具有选择性的抑制剂，其中选择性归因于抑制剂金属结合部分上的取代基与 HDAC 酶结构的 14-Å 内腔中的残基之间的相互作用。基于这一早期工作，我们合成并测试了在异羟肟酸金属结合部分上具有取代基的 SAHA 类似物。与 SAHA 相比，N 取代的 SAHA 类似物显示出较低的效力和溶解度，但具有更高的选择性。对接研究表明，N-取代基进入 14-Å 内腔以优先抑制 HDAC1。这些对 N 取代的 SAHA 类似物的研究与利用 HDAC 蛋白的 14 Å 内腔产生 HDAC1/2 选择性抑制剂的策略一致。