biostudies-literatureAzizi SASwiss National Science FoundationNIDDK NIH HHSNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institute of General Medical SciencesNIGMS NIH HHS1648-1654https://www.ebi.ac.uk/biostudies/studies/S-EPMC9575173biostudies-literatureUnknown13(10)Protein S-acylation is a dynamic and reversible lipid post-translational modification that can affect the activity, stability, localization, and interactions of target proteins. Lipid modification occurs on cysteine residues via a thioester bond and in humans is mediated by 23 Asp-His-His-Cys domain-containing protein acyltransferases (DHHC-PATs). The DHHC-PATs have well-known roles in physiology and disease, but much remains to be discovered about their biological function and therapeutic potential. We recently developed cyanomyracrylamide (<b>CMA</b>), an acrylamide-based DHHC inhibitor with key improvements over existing inhibitors. Here we conduct a structure-activity relationship (SAR) study of <b>CMA</b> and its acrylamide derivatives against zDHHC20, the most structurally characteriACS medicinal chemistry lettersCharting the Chemical Space of Acrylamide-Based Inhibitors of zDHHC20.PMC9575173F30 DK125088P2BEP2_188250R35 GM119840T32 GM007281Lan TDickinson BCAzizi SAQiu TDelalande CfalseCharting the Chemical Space of Acrylamide-Based Inhibitors of zDHHC20.Protein S-acylation is a dynamic and reversible lipid post-translational modification that can affect the activity, stability, localization, and interactions of target proteins. Lipid modification occurs on cysteine residues via a thioester bond and in humans is mediated by 23 Asp-His-His-Cys domain-containing protein acyltransferases (DHHC-PATs). The DHHC-PATs have well-known roles in physiology and disease, but much remains to be discovered about their biological function and therapeutic potential. We recently developed cyanomyracrylamide (<b>CMA</b>), an acrylamide-based DHHC inhibitor with key improvements over existing inhibitors. Here we conduct a structure-activity relationship (SAR) study of <b>CMA</b> and its acrylamide derivatives against zDHHC20, the most structurally characteri2022-01-01T00:00:00Z2022 Oct2026-05-28T02:15:35.398Z2025-04-04T11:00:30.6ZS-EPMC95751733626240410.1021/acsmedchemlett.2c00336