Development of 1,2,4-Oxadiazoles as Potent and Selective Inhibitors of the Human Deacetylase Sirtuin 2: Structure–Activity Relationship, X‑ray Crystal Structure, and Anticancer Activity

Sirt2
is a target for the treatment of neurological, metabolic,
and age-related diseases including cancer. Here we report a series
of Sirt2 inhibitors based on the 1,2,4-oxadiazole scaffold. These
compounds are potent Sirt2 inhibitors active at single-digit μM
level by using the Sirt2 substrate α-tubulin-acetylLys40 peptide
and inactive up to 100 μM against Sirt1, -3, and -5 (deacetylase
and desuccinylase activities). Their mechanism of inhibition is uncompetitive
toward both the peptide substrate and NAD+, and the crystal
structure of a 1,2,4-oxadiazole analog in complex with Sirt2 and ADP-ribose
reveals its orientation in a still unexplored subcavity useful for
further inhibitor development. Tested in leukemia cell lines, 35 and 39 induced apoptosis and/or showed antiproliferative
effects at 10 or 25 μM after 48 h. Western blot analyses confirmed
the involvement of Sirt2 inhibition for their effects in NB4 and in
U937 cells. Our results provide novel Sirt2 inhibitors with a compact
scaffold and structural insights for further inhibitor improvement.