Negmeldin Ahmed T, Knoff Joseph R, Pflum Mary Kay H
Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, MI 48202, United States; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, MI 48202, United States.
Eur J Med Chem. 2018 Jan 1;143:1790-1806. doi: 10.1016/j.ejmech.2017.10.076. Epub 2017 Oct 31.
Histone deacetylase (HDAC) enzymes govern the post-translational acetylation state of lysine residues on protein substrates, leading to regulatory changes in cell function. Due to their role in cancers, HDAC proteins have emerged as promising targets for cancer treatment. Four HDAC inhibitors have been approved as anti-cancer therapeutics, including SAHA (Suberoylanilide hydroxamic acid, Vorinostat, Zolinza). SAHA is a nonselective HDAC inhibitor that targets most of the eleven HDAC isoforms. The nonselectivity of SAHA might account for its clinical side effects, but certainly limits its use as a chemical tool to study cancer-related HDAC cell biology. Herein, the nonselective HDAC inhibitor SAHA was modified at the C4 position of the linker to explore activity and selectivity. Several C4-modified SAHA analogs exhibited dual HDAC6/8 selectivity. Interestingly, (R)-C4-benzyl SAHA displayed 520- to 1300-fold selectivity for HDAC6 and HDAC8 over HDAC1, 2, and 3, with IC values of 48 and 27 nM with HDAC6 and 8, respectively. In cellulo testing of the inhibitors was consistent with the observed in vitro selectivity. Docking studies provided a structural rationale for selectivity. The C4-SAHA analogs represent useful chemical tools to understand the role of HDAC6 and HDAC8 in cancer biology and exciting lead compounds for targeting of both HDAC6 and HDAC8 in various cancers.
组蛋白去乙酰化酶（HDAC）可调控蛋白质底物上赖氨酸残基的翻译后乙酰化状态，从而导致细胞功能发生调节性变化。由于其在癌症中的作用，HDAC蛋白已成为癌症治疗的有前景的靶点。四种HDAC抑制剂已被批准作为抗癌治疗药物，包括SAHA（辛二酰苯胺异羟肟酸，伏立诺他，Zolinza）。SAHA是一种非选择性HDAC抑制剂，可靶向11种HDAC亚型中的大多数。SAHA的非选择性可能是其临床副作用的原因，但肯定限制了其作为研究癌症相关HDAC细胞生物学的化学工具的用途。在此，对非选择性HDAC抑制剂SAHA的连接子C4位置进行修饰，以探索其活性和选择性。几种C4修饰的SAHA类似物表现出对HDAC6/8的双重选择性。有趣的是，（R）-C4-苄基SAHA对HDAC6和HDAC8的选择性比对HDAC1、2和3高520至1300倍，对HDAC6和8的IC值分别为48和27 nM。抑制剂的细胞内测试与观察到的体外选择性一致。对接研究为选择性提供了结构依据。C4-SAHA类似物是了解HDAC6和HDAC8在癌症生物学中的作用的有用化学工具，也是在各种癌症中靶向HDAC6和HDAC8的令人兴奋的先导化合物。
