Targeted Protein Degradation by Small Molecules

Abstract

Protein homeostasis networks are highly regulated systems responsible for maintaining the health and productivity of cells. Whereas therapeutics have been developed to disrupt protein homeostasis, more recently identified techniques have been used to repurpose homeostatic networks to effect degradation of disease-relevant proteins. Here, we review recent advances in the use of small molecules to degrade proteins in a selective manner. First, we highlight all-small-molecule techniques with direct clinical application. Second, we describe techniques that may find broader acceptance in the biomedical research community that require little or no synthetic chemistry. In addition to serving as innovative research tools, these new approaches to control intracellular protein levels offer the potential to develop novel therapeutics targeting proteins that are not currently pharmaceutically vulnerable.

Targeted Protein Degradation: from Chemical Biology to Drug Discovery

“…transcription factors, scaffolding proteins or non-enzymatic proteins inside the cell (Hopkins and Groom, 2002; Wells and McClendon, 2007; Surade and Blundell, 2012; Lazo and Sharlow, 2016). Small molecule induced proteolysis offers an alternative strategy as it combines the drug-like properties of small molecules with an event -driven intracellular control of proteins levels as transient binding can already be sufficient for effective target degradation (Toure and Crews, 2016; Bondeson and Crews, 2017; Lai and Crews, 2017; Ottis and Crews, 2017; Salami and Crews, 2017). This approach offers the potential to reach beyond the limitations of traditional drug discovery and target the “undruggable” proteome, as binding to the protein of interest (POI) does not need to be connected to inhibition of the POI since it induces its removal from the system.…”

“…Recently, however, small molecules have been used to selectively induce the degradation of a variety of interesting target proteins (Bondeson et al, 2015; Winter et al, 2015). This technique, called PROteolysis-TArgeting Chimeras (PROTACs), provides a highly promising new modality for drug discovery and is capable of reaching beyond the boundaries posed by traditional drug discovery (Toure and Crews, 2016; Bondeson and Crews, 2017; Lai and Crews, 2017; Ottis and Crews, 2017; Salami and Crews, 2017). This review summarizes recent advances in small molecule-induced proteolysis of targeted proteins and provides an outlook on future opportunities and challenges in the field.…”

The PROTAC technology in drug development

“…This proteolysis targeting chimera (PROTAC) consists of a ligand on an E3 ubiquitin ligase, a linker, and a ligand on targeted protein could be able to mediate the degradation of multiple molecules of RIPK2 via ubiquitin-proteasomal pathway. 15,52 To overcome the shortage of insufficient membrane permeability and stability of the peptide-based PROTACs, Hashimoto group focused on using cIAP1, which promotes ubiquitination and proteasomal degradation of interacting proteins. 44 Many of the small molecule-based PROTACs have been developed intensively to target the BET family proteins.…”

PROTACs: An Emerging Targeting Technique for Protein Degradation in Drug Discovery

“…PROTACs are hetero‐bifunctional molecules that contain a ligand for recruiting an E3 ligase, a linker, and another ligand to bind with the target protein for degradation (Figure a) . Thus, PROTACs are capable of specifically binding with both the target protein and the E3 ligase simultaneously and hijacking them together, leading to the formation of a ternary complex.…”

“…Thus, PROTACs are capable of specifically binding with both the target protein and the E3 ligase simultaneously and hijacking them together, leading to the formation of a ternary complex. As a result, by recruiting an E3 ubiquitin ligase, ubiquitin can be transferred from an E2 to the target protein, which is eventually degraded by the proteasome (Figure b) …”