Lin Xianfeng, Chen Wenming, Qiu Zongxing, Guo Lei, Zhu Wei, Li Wentao, Wang Zhanguo, Zhang Weixing, Zhang Zhenshan, Rong Yiping, Zhang Meifang, Yu Lingjie, Zhong Sheng, Zhao Rong, Wu Xihan, Wong Jason C, Tang Guozhi
Roche Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai, 720 Cailun Road, Shanghai 201203, China.
J Med Chem. 2015 Mar 26;58(6):2809-20. doi: 10.1021/jm502011f. Epub 2015 Mar 13.
Histone deacetylase 6 (HDAC6) removes the acetyl group from lysine residues in a number of non-histone substrates and plays important roles in microtubule dynamics and chaperone activities. There is growing interest in identifying HDAC6-selective inhibitors as chemical biology tools and ultimately as new therapeutic agents. Herein we report the design, synthesis, and phenotypic screening of a novel class of 3-aminopyrrolidinone-based hydroxamic acids as HDAC6 inhibitors. In particular, the α-methyl-substituted enantiomer 33 (3-S) showed significant in-cell tubulin acetylation (Tub-Ac) with an EC50 of 0.30 μM but limited impact on p21 levels at various concentrations. In enzyme inhibition assays, 33 demonstrated high selectivity for HDAC6 with an IC50 of 0.017 μM and selectivity indexes of 10 against HDAC8 and over 4000 against HDAC1-3 isoforms. Moreover, 33 has suitable drug metabolism and pharmacokinetics properties compared with other hydroxamic acid-based HDAC inhibitors, warranting further biological studies and development as a selective HDAC6 inhibitor.
组蛋白去乙酰化酶6（HDAC6）可从多种非组蛋白底物的赖氨酸残基上去除乙酰基，并在微管动力学和伴侣活性中发挥重要作用。人们越来越有兴趣鉴定HDAC6选择性抑制剂，将其作为化学生物学工具，并最终作为新型治疗药物。在此，我们报告了一类新型的基于3-氨基吡咯烷酮的异羟肟酸作为HDAC6抑制剂的设计、合成及表型筛选。特别地，α-甲基取代的对映体33（3-S）在细胞内显示出显著的微管蛋白乙酰化（Tub-Ac），EC50为0.30μM，但在不同浓度下对p21水平的影响有限。在酶抑制试验中，33对HDAC6表现出高选择性，IC50为0.017μM，对HDAC8的选择性指数为10，对HDAC1-3亚型的选择性指数超过4000。此外，与其他基于异羟肟酸的HDAC抑制剂相比，33具有合适的药物代谢和药代动力学性质，值得作为选择性HDAC6抑制剂进行进一步的生物学研究和开发。
