Targeting protein palmitoylation: selective inhibitors and implications in disease

Expert Opin Drug Discov. 2014 Sep;9(9):1005-19. doi: 10.1517/17460441.2014.933802. Epub 2014 Jun 26.


Introduction: Palmitoylation describes the enzymatic attachment of the 16-carbon fatty acid, palmitate, to specific cysteines of proteins via a labile thioester bond. This post-translational modification increases the lipophilicity of the modified protein, thus regulating its subcellular distribution and function. The transfer of palmitate to a substrate is mediated by palmitoyl acyltransferases (PATs), while depalmitoylation is catalyzed by acyl protein thioesterases (APTs). Nearly one-third of the 23 genes that encode PATs are linked to human diseases, representing important targets for drug development.

Areas covered: In this review, the authors summarize the recent technical advances in the field of palmitoylation and how they will affect our ability to understand palmitoylation and its relevance to human disease. They also review the current literature describing existing palmitoylation inhibitors. The aim of this article is to increase the awareness of the importance of palmitoylation in disease by reviewing the recent progress made in identifying pharmacological modulators of PATs/APTs. It also aims to provide suggestions for general considerations in the development of selective and potent PAT inhibitors.

Expert opinion: Developing therapeutically useful pharmacological modulators of palmitoylation will require that they be developed within the context of well-characterized PAT/APT-related signaling systems. The successful development of potent, specific drugs in similarly complex systems suggests that development of useful drugs targeting PATs is feasible.

Keywords: Asp-His-His-Cys; Asp-His-His-Cys 2; acyl protein thioesterases; cancer; cysteine; palmitoyl acyltransferases; palmitoylation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Acyltransferases / antagonists & inhibitors*
  • Acyltransferases / genetics
  • Acyltransferases / metabolism
  • Animals
  • Drug Design*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Lipoylation / drug effects*
  • Molecular Targeted Therapy
  • Protein Processing, Post-Translational
  • Signal Transduction / drug effects
  • Substrate Specificity


  • Enzyme Inhibitors
  • Acyltransferases