ABSTRACT
Inhibitors of histone deacetylases (HDAC) are emerging as a promising class of anti-cancer agents. The mercaptoacetoamide-based inhibitors are reported to be less toxic than hydroxamate and are worthy of further consideration. Therefore, we have designed a series of analogs as potential inhibitors of HDACs, in which the mercaptoacetamide group was replaced by (mercaptomethyl)fluoroalkene, and their HDAC inhibitory activity was evaluated. Subnanomolar inhibition was observed for all synthetic compounds.
Subject(s)
Histone Deacetylase Inhibitors/pharmacology , Hydrocarbons, Fluorinated/chemistry , Thioacetamide/pharmacology , Drug Design , HeLa Cells , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/chemistry , Humans , Molecular Structure , Stereoisomerism , Structure-Activity Relationship , Thioacetamide/analogs & derivatives , Thioacetamide/chemistryABSTRACT
Human ubiquitin ligase HRD1 is involved in endoplasmic reticulum-associated degradation (ERAD). We recently reported that HRD1 interacts with Parkin-associated endothelin receptor-like receptor (Pael-R), a substrate of Parkin, and promotes Pael-R degradation, resulting in the protection of cells from the lethal accumulation of Pael-R. However, except for RING-finger domain that is necessary for ubiquitin ligase activity, the roles of other human HRD1 domains are unclear. Here, we show that the proline-rich domain of HRD1 is necessary to promote the degradation of Pael-R and that the protein's transmembrane domain is necessary to transfer Pael-R from the endoplasmic reticulum (ER) to the cytosol. A HRD1 mutant defective in the transmembrane domain is markedly more unstable than wild-type HRD1. These results suggest that HRD1 has diverse functions besides ubiquitin ligase activity.
