Targeted protein degradation: current and future challenges

Abstract

Traditional approaches in the development of small-molecule drugs typically aim to inhibit the biochemical activity of functional protein domains. In contrast, targeted protein degradation aims to reduce overall levels of disease-relevant proteins. Mechanistically, this can be achieved via chemical ligands that induce molecular proximity between an E3 ubiquitin ligase and a protein of interest, leading to ubiquitination and degradation of the protein of interest. This paradigm-shifting pharmacology promises to address several limitations inherent to conventional inhibitor design. Most notably, targeted protein degradation has the potential not only to expand the druggable proteome beyond the reach of traditional competitive inhibitors but also to develop therapeutic strategies of unmatched selectivity. This review briefly summarizes key challenges that remain to be addressed to deliver on these promises and to realize the full therapeutic potential of pharmacologic modulation of protein degradation pathways.

Keywords: Chemical biology; E3 ligase; Molecular glues; PROTACs; Targeted protein degradation.

Figure 1. Schematic comparison of molecular glues and PROTACs.

(a) Molecular glues are monovalent compounds that induce the dimerization of two proteins (here: an E3 ligase substrate receptor and a neosubstrate). Compound-induced proximity is often characterized by multiple interactions between the two proteins, resulting in high binding cooperativity. (b) PROTACs are heterobifunctional degraders that can individually bind to the E3 ligase and the protein of interest. Simultaneous binding induces molecular proximity and ensuing ubiquitination and degradation of the POI. In contrast to MGs, PROTAC-mediated dimerization is less dependent on compatible protein surfaces and associated binding cooperativity. PROTAC, proteolysis targeting chimeras; MG, molecular glue; POI, protein of interest.

Figure 2. Comparison of DCAF15- and CRBN-based molecular glue degraders.

(a) A structure of DCAF15 (PDB: 6PAI) bound to indisulam, the RRM2 domain of RBM39 and DDB1 aligned with a structure of DDB1:CUL4A:RBX1 (PDB 6PAI). (b) A structure of CRBN (PDB: 6H0F) in complex with pomalidomide, the ZF2 domain of IKZF1 and DDB1 aligned with a structure of DDB1:CUL4A:RBX1 (PDB 6PAI). (c) Comparison of general properties of DCAF15- and CRBN-based molecular glues.