Design, Synthesis, and Biological Evaluation of Tetrahydroisoquinoline-Based Histone Deacetylase 8 Selective Inhibitors

作者：Taha Taha Y; Aboukhatwa Shaimaa M; Knopp Rachel C; Ikegaki Naohiko; Abdelkarim Hazem; Neerasa Jayaprakash; Lu Yunlong; Neelarapu Raghupathi; Hanigan Thomas W; Thatcher Gregory R J; Petukhov Pavel A^*

来源：ACS Medicinal Chemistry Letters, 2017, 8(8): 824-829.

DOI：10.1021/acsmedchemlett.7b00126

• Histone deacetylase
• HDAC8
• hydroxamate
• inhibitor
• tetrahydroisoquinoline

Histone deacetylase 8 (HDAC8) is a promising drug target for multiple therapeutic applications. Here, we describe the modeling, design, synthesis, and biological evaluation of a novel series of C1-substituted tetrahydroisoquinoline (TIQ)-based HDAC8 inhibitors. Minimization of entropic loss upon ligand binding and use of the unique HDAC8 open conformation of the binding site yielded a successful strategy for improvement of both HDAC8 potency and selectivity. The TIQ-based 3g and 3n exhibited the highest 82 and 55 nM HDAC8 potency and 330- and 135-fold selectivity over HDAC1, respectively. Selectivity over other class I isoforms was comparable or better, whereas inhibition of HDAC6, a class II HDAC isoform, was below 50% at 10 mu M. The cytotoxicity of 3g and 3n was evaluated in neuroblastoma cell lines, and 3n displayed concentration-dependent cytotoxicity similar to or better than that of PCI-34051. The selectivity of 3g and 3n was confirmed in SH-SY5Y cells as both did not increase the acetylation of histone H3 and alpha-tubulin. Discovery of the novel TIQ chemotype paves the way for the development of HDAC8 selective inhibitors for therapeutic applications.

• 出版日期2017-8