Thienopyrimidinone Based Sirtuin‑2 (SIRT2)-Selective Inhibitors Bind in the Ligand Induced Selectivity Pocket

Sirtuins
(SIRTs) are NAD-dependent deacylases, known to be involved in a variety
of pathophysiological processes and thus remain promising therapeutic
targets for further validation. Previously, we reported a novel thienopyrimidinone
SIRT2 inhibitor with good potency and excellent selectivity for SIRT2.
Herein, we report an extensive SAR study of this chemical series and
identify the key pharmacophoric elements and physiochemical properties
that underpin the excellent activity observed. New analogues have
been identified with submicromolar SIRT2 inhibtory activity and good
to excellent SIRT2 subtype-selectivity. Importantly, we report a cocrystal
structure of one of our compounds (29c) bound to SIRT2.
This reveals our series to induce the formation of a previously reported selectivity
pocket but to bind in an inverted fashion to what might be intuitively
expected. We believe these findings will contribute significantly
to an understanding of the mechanism of action of SIRT2 inhibitors
and to the identification of refined, second generation inhibitors.