Replacement of the hydroxamic acid group in the selective HDAC8 inhibitor PCI-34051

被引：1

作者：

Long, Keith ^{[1
]}

Close, David A. ^{[1
]}

Johnston, Paul A. ^{[1
]}

Huryn, Donna M. ^{[1
,2
]}

机构：

[1] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA

[2] Univ Penn, Dept Chem, Philadelphia, PA 19106 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2024年 / 108卷

基金：

美国国家卫生研究院;

关键词：

Histone deacetylase 8; PCI-34051; Hydroxamic acid; Isosteric replacement; HISTONE DEACETYLASE; POTENT; MUTAGENICITY;

D O I：

10.1016/j.bmcl.2024.129810

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

PCI-34051 is a valuable tool to interrogate the therapeutic effects of selective inhibition of HDAC8. However, it has not advanced to clinical trials, perhaps due to poor PK or off-target effects. We hypothesized that the presence of a hydroxamic acid (HA) group in PCI-34051 contributed to its lack of advancement. Therefore, we replaced the HA in the PCI-34051 scaffold with a series of moieties that have the potential to bind to Zn and evaluated their activity in a HDAC8 assay. Surprisingly, none of the replacements effectively mimicked the HA, and analogs lost significant potency. Evaluation of the analogs' affinity to Zn indicated that none had affinity for Zn within the same range as the HA. These studies point to the difficulty in the application of bioisosteric replacements for Zn binding motifs.

引用

页数：5

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