Reversible Covalent PROTACs: Novel and Efficient Targeted Degradation Strategy

Abstract

The proteolysis targeting chimeras (PROTACs), which are composed of a target protein binding moiety, a linker, and an E3 ubiquitin ligase binder, have been a promising strategy for drug design and discovery. Given the advantages of potency, selectivity, and drug resistance over inhibitors, several PROTACs have been reported in literature, which mostly focus on noncovalent or irreversible covalent binding to the target proteins. However, it must be noted that noncovalent or irreversible PROTACs have several drawbacks such as weak binding affinity and unpredictable off-target effects. Reversible covalent PROTACs, with properties of enhanced potency, selectivity, and long duration of action, have attracted an increasing amount of attention. Here, we propose a comparison between these three patterns and highlight that reversible covalent PROTACs could pave the way for a wide variety of challenging target degradations.

Advanced approaches of developing targeted covalent drugs

“…Duan et al divided PROTACs into three types depending on their binding mode to the E3 ligase: irreversible covalent, reversible non-covalent and reversible covalent binding. 12 To date, most reported PROTACs bind to target proteins by means of a reversible non-covalent pattern, e.g. the first oral PROTACs (ARV-110 and ARV-471) showed encouraging results in clinical trials for prostate and breast cancer treatment.…”

“…Several new techniques and multidisciplinary ideas including proteolysis targeting chimeras (PROTACs) and peptide drugs currently promote the development of either reversible or irreversible covalent inhibitors also. 12,13 The strategy employed depends on prior knowledge and structural tolerance of the scaffold and target when processing a new project.…”

Recent Advances in PROTAC Technology Toward New Therapeutic Modalities

“…[15,16,17] The low specificity of conventional PROTACs sometimes leads to the degradation of several protein subtypes within the same protein family, [18] and this remains a disadvantage of conventional designs. [19] Conventional PROTACs are designed using reversible non-covalent warheads. To increase POI selectivity, more recent PROTAC designs incorporate covalent warheads.…”

Covalent PROTAC design method based on a sulfonyl pyridone probe

“…2,3 Covalent PROTACs have the potential to diversify the available targets and E3 ligases, significantly expanding the options for targeted protein degradation. 4,5 They also offer the potential to expedite the formation of crucial ternary complexes within the cellular environment, making them a promising approach. Furthermore, covalent PROTACs can introduce an additional layer of specificity to the degrader, enhancing its precision in modulating specific protein targets.…”