The “holy grail” of pharmacology is the ability to specifically target the cell type responsible for a disease. Given that many drugs act intracellularly on targets that are active in most cells in the body, targeting specificity could be used to reduce unwanted side effects and toxicities. Needham et al. have investigated the development of a chemical platform that enhances the potency and delivery of small-molecule drugs to intracellular targets. Attaching a small esterase-sensitive chemical motif (ESM) that is selectively hydrolyzed by an intracellular carboxylesterase human carboxylesterase-1 (hCE1) allows small-molecule inhibitors to be released as charged, pharmacologically active drugs specifically in monocytes and macrophages. An ESM-linked histone deacetylase (HDAC) inhibitor showed impressive anticytokine and antiarthritic activity in hCE1 knock-in mice. The activity of the HDAC ESM (CHR4487) was demonstrated in human whole blood with anticytokine activity observed at concentrations 1000 times lower than those needed to affect other cell types. Such cell specificity provides a greater therapeutic index for HDAC ESMs versus the parental HDAC inhibitors in vivo. Chemical conjugates of this type, providing specificity and greater TIs, could also be harnessed with other enzymes with acceptable expression profiles.
See article at J Pharmacol Exp Ther 2011, 339:132–142.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics