Showing papers by "Robert W. Myers published in 2020"
TL;DR: A series of selective and potent class I HDAC inhibitors based on aryl ketones as a zinc binding group, which reversed HIV latency using a Jurkat model of HIV latency in 2C4 cells are reported.
Abstract: HIV persistence in latently infected, resting CD4+ T cells is broadly considered a barrier to eradicate HIV. Activation of the provirus using latency-reversing agents (LRAs) followed by immune-mediated clearance to purge reservoirs has been touted as a promising therapeutic approach. Histone deacetylases (HDACs) and histone acetyltransferases (HATs) control the acetylation level of lysine residues in histones to regulate the gene transcription. Several clinical HDAC inhibitors had been examined as LRAs, which induced HIV activation in vitro and in vivo. Here we report the discovery of a series of selective and potent class I HDAC inhibitors based on aryl ketones as a zinc binding group, which reversed HIV latency using a Jurkat model of HIV latency in 2C4 cells. The SAR led to the discovery of a highly selective class I HDAC inhibitor 10 with excellent potency. HDACi 10 induces the HIV gag P24 protein in patient latent CD4+ T cells.
18 citations
TL;DR: A novel series of ethyl ketone basedHDACs 1, 2, and 3 selective inhibitors have been identified with good enzymatic and cellular activity and high selectivity over HDACs 6 and 8, which contain a spirobicyclic group in the amide region.
17 citations
TL;DR: The synthesis and SAR development of a trisubstituted imidazole HDAC inhibitor is described, which provided insight into binding mode and supported design rational.
12 citations