Abstract
Proteolysis targeting chimeras (PROTACs) represent a promising class of hetero-bivalent molecules that facilitate ubiquitination of a target protein by simultaneously binding and bringing together both the E3 enzyme and the target. These compounds consist of three structural components: two ligands one of which binds the protein of interest (POI) while the other binds an E3 ubiquitin ligase to promote POI ubiquitination, and a linker connecting both moieties. Recent developments in the field highlight the fact that linker composition and length play a crucial role in achieving optimal PROTAC properties, modulate binding kinetics and substantially impacts the potency and selectivity. In this review, the authors briefly discuss the recent findings in PROTAC design approaches with focus on the linker. For each PROTAC such linker parameters as chemical nature, length, hydrophilicity and rigidity have to be optimized to achieve improved stability, bioavailability cell membrane permeability and suitable spatial orientation between the target POI and the E3 ubiquitin ligase. Thus rational linker design with respect to composition, length and attachment sites is essential for the development of potent PROTAC compounds. Computer-aided design and novel innovative linker strategies, such as PROTAC shortening, photo-switchable PROTACs, in-cell click-formed CLIPTACs, “click chemistry” approaches are also discussed in the review.
Highlights
Proteolysis targeting chimeras (PROTACs), known as degraders, degronimids, protein domain parser (PDPs), specific and non-genetic IAP-dependent protein erasers (SNIPERs), represent a promising class of hetero-bivalent molecules that promote ubiquitination and subsequent proteasomal degradation of the target protein
Proteolysis targeting chimeras (PROTACs) represent a promising class of hetero-bivalent molecules that facilitate ubiquitination of a target protein by simultaneously binding and bringing together both the E3 enzyme and the target. These compounds consist of three structural components: two ligands one of which binds the protein of interest (POI) while the other binds an E3 ubiquitin ligase to promote POI ubiquitination, and a linker connecting both moieties
PROTACs consist of three structural components that allow bringing together the E3 ubiquitin ligase and the target: a ligand targeting the protein of interest (POI), a second ligand binding an E3 ubiquitin
Summary
Proteolysis targeting chimeras (PROTACs), known as degraders, degronimids, protein domain parser (PDPs), specific and non-genetic IAP-dependent protein erasers (SNIPERs), represent a promising class of hetero-bivalent molecules that promote ubiquitination and subsequent proteasomal degradation of the target protein. This approach, sometimes called as “chemical knockdown”, enables ligand-induced degradation of specific endogenous proteins [2]. The main advantage of PROTACs is their catalytic nature that enables sub-stoichiometric and catalytic enzymatic removal of substrate POIs rather than their inhibition via occupation of the binding site (Figure 1) This strategy has been extensively used in degrading a variety of therapeutically relevant proteins, transcriptional regulators and hormone receptors. For each PROTAC compound such parameters of the linker as chemical nature, length, hydrophilicity and rigidity have to be optimized to achieve improved cell permeability and suitable spatial orientation between the target POI and the E3 ubiquitin ligase [3, 4]. Most linkers contain a combination of hydrophobic (unsaturated alkanes) and hydrophilic moieties (PEGs, piperidines, amides, triazoles, etc.) to balance logP of the resulting compounds [11, 12]
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