Identification of Diketopiperazine-Containing 2‑Anilinobenzamides
as Potent Sirtuin 2 (SIRT2)-Selective Inhibitors Targeting the “Selectivity
Pocket”, Substrate-Binding Site, and NAD+‑Binding
Site
The NAD+-dependent deacetylase SIRT2 represents an attractive
target for drug development. Here, we designed and synthesized drug-like
SIRT2-selective inhibitors based on an analysis of the putative binding
modes of recently reported SIRT2-selective inhibitors and evaluated
their SIRT2-inhibitory activity. This led us to develop a more drug-like
diketopiperazine structure as a “hydrogen bond (H-bond) hunter”
to target the substrate-binding site of SIRT2. Thioamide 53, a conjugate of diketopiperazine and 2-anilinobenzamide which is
expected to occupy the “selectivity pocket” of SIRT2,
exhibited potent SIRT2-selective inhibition. Inhibition of SIRT2 by 53 was mediated by the formation of a 53-ADP-ribose
conjugate, suggesting that 53 is a mechanism-based inhibitor
targeting the “selectivity pocket”, substrate-binding
site, and NAD+-binding site. Furthermore, 53 showed potent antiproliferative activity toward breast cancer cells
and promoted neurite outgrowth of Neuro-2a cells. These findings should
pave the way for the discovery of novel therapeutic agents for cancer
and neurological disorders.