Discovery of macrocyclic HDACs 1, 2, and 3 selective inhibitors for HIV latency reactivation

Abstract

A series of unique macrocyclic HDACs 1, 2, and 3 selective inhibitors were identified with good enzymatic activity and high selectivity over HDACs 6 and 8. These macrocyclic HDAC inhibitors used an ethyl ketone as the zinc-binding group. Compounds 25 and 26 stood out as leads due to their low double-digit nM EC₅₀s in the 2C4 cell-based HIV latency reactivation assay. The PK profiles of these macrocyclic HDAC inhibitors still needed improvement.

Keywords: HDAC inhibitor; HIV infection; HIV latency reactivation; Macrocycle; Selective HDAC inhibitor.