Substrate-Guided Development of HDAC11-Selective Inhibitors Featuring α‑Amino Amide Zinc-Binding Groups

TL;DR

This paper describes the development of a new HDAC11 inhibitor with a unique zinc-binding group and selectivity tail, offering a promising approach for targeting defatty-acylase activity.

Contribution

The study introduces a novel HDAC11-selective inhibitor with an α-amino amide zinc-binding group and a fatty-acylated lysine selectivity tail.

Findings

Compound 31 inhibits HDAC11 at low nanomolar concentrations without affecting other HDACs.

The design strategy enables straightforward development of selective defatty-acylase inhibitors.

Abstract

Histone deacetylases (HDACs) play a pivotal role in various
biological
pathways and represent interesting drug targets. Therefore, HDAC inhibitors
(HDACi) with high isoform selectivity and a zinc-binding group different
from hydroxamic acid, because of its low metabolic stability, are
required. HDAC11, as a highly potent defatty-acylase, differs from
other HDACs in its substrate preference. Starting from this finding,
we developed specific inhibitors for HDAC11 based on a peptide containing
a fatty-acylated lysine side chain as the selectivity tail. The introduction
of different heteroatoms at the fatty acyl residue was used to generate
potent zinc-binding groups in combination with the scissile amide
bond, as well as to suppress substrate properties of the resulting
compounds. Further optimization resulted in a highly potent and selective
HDAC11 inhibitor 31, which exhibits low nanomolar inhibition
against HDAC11 without targeting other HDACs and is active in cells.
The data presented here may help expand the range of zinc-binding
groups utilized in HDAC inhibitors. Furthermore, the concept of the
selectivity tail was demonstrated to facilitate straightforward access
to selective defatty-acylase inhibitors.

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