Inducing the Degradation of Disease-Related Proteins Using Heterobifunctional Molecules
Open Access
Abstract
Current drug development strategies that target either enzymatic or receptor proteins for which specific small molecule ligands can be designed for modulation, result in a large portion of the proteome being overlooked as undruggable. The recruitment of natural degradation cascades for targeted protein removal using heterobifunctional molecules (or degraders) provides a likely avenue to expand the druggable proteome. In this review, we discuss the use of this drug development strategy in relation to degradation cascade-recruiting mechanisms and successfully targeted disease-related proteins. Essential characteristics to be considered in degrader design are deliberated upon and future development challenges mentioned.Keywords
Funding Information
- National Research Foundation (DAAD170613239977)
- Deutscher Akademischer Austauschdienst (DAAD170613239977)
This publication has 85 references indexed in Scilit:
- Expanding the Number of ‘Druggable’ Targets: Non‐Enzymes and Protein–Protein InteractionsChemical Biology & Drug Design, 2012
- Mining and characterization of ubiquitin E3 ligases expressed in the mouse testisBMC Genomics, 2012
- Inhibitor Mediated Protein DegradationChemistry & Biology, 2012
- Small-molecule hydrophobic tagging–induced degradation of HaloTag fusion proteinsNature Chemical Biology, 2011
- Specific degradation of CRABP-II via cIAP1-mediated ubiquitylation induced by hybrid molecules that crosslink cIAP1 and the target proteinFEBS Letters, 2011
- Chaperone-mediated autophagy at a glanceJournal of Cell Science, 2011
- Chemical Inducers of Targeted Protein DegradationJournal of Biological Chemistry, 2010
- Heat Shock Protein 70 (Hsp70) as an Emerging Drug TargetJournal of Medicinal Chemistry, 2010
- Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomicsBioorganic & Medicinal Chemistry Letters, 2008
- Targeted Degradation of the Aryl Hydrocarbon Receptor by the PROTAC Approach: A Useful Chemical Genetic ToolChemBioChem, 2007