Click Chemistry and Targeted Degradation: A Winning Combination for Medicinal Chemists?

Abstract

Click chemistry is universally recognized as a powerful strategy for the fast and precise assembly of diverse building blocks. Targeted Protein Degradation (TPD) is a new therapeutic modality based on heterobifunctional small‐molecule degraders that provides new opportunities to medicinal chemists dealing with undruggable targets and incurable diseases. Here, we highlight how very recently the TPD field and that of click chemistry have merged, opening up the possibility for fine‐tuning the properties of a degrader, chemically assembled through a “click” synthesis. By reviewing concrete examples, we want to provide the reader with the insight that the application of click and bioorthogonal chemistry in the TDP field may be a winning combination.

Development of Biocompatible Cu(I)‐Microdevices for Bioorthogonal Uncaging and Click Reactions

“…In our opinion, this competition phenomenon, which is analogous to the hook effect, becomes a limitation for the application of in situ‐ assembled PROTACs to induce site‐specific protein degradation as long as the precursors are free to interact independently with their targets. Alternative strategies capable of accelerating the PROTAC assembly [68,69] might reduce the impact of this situation if combined with spatiotemporal control.…”

Accelerating PROTACs Discovery Through a Direct‐to‐Biology Platform Enabled by Modular Photoclick Chemistry

“…[ 24 , 25 , 26 , 27 , 28 , 29 ] Notably, in recent years, click chemistry has been employed for the construction of PROTACs and fine‐tuning the properties of the designed degraders. [ 34 , 35 ] However, this synthetic strategy was mainly used for a single experiment of PROTAC synthesis and still required further product purification processes to remove the metal catalyst and ligands. [ 18 , 36 , 37 , 38 ] We reasoned that several factors are required for the successful implementation of this direct‐to‐biology strategy: i) PROTACs are heterobifunctional molecules consisting of a target protein ligand, a connecting linker, and an E3 ligand, Therefore, the fragments for PROTAC library synthesis should be readily accessible; ii) The high‐throughput synthesis of PROTACs should be conducted without the use of toxic metal catalysts and additional chemical reagents or ligands, with the goal of minimizing toxicity to biological systems; iii) The by‐products generated during synthetic steps ideally should not interfere with subsequent bioassays; for instance, by‐products like water are considered acceptable; iv) The multi‐step synthesis reactions should be highly efficient and compatible in plates without the need for further purification steps, which ensures a seamless synthesis‐bioassay process; v) Due to the critical roles that linker structures (e.g., linkage site and linker length) play in the bioactivity of degraders, [ 14 , 15 , 16 ] the linker should be stable and exhibit diversity in linkages.…”

Restraining the power of Proteolysis Targeting Chimeras in the cage: A necessary and important refinement for therapeutic safety

“…The advent of PROTACs is rooted in the strategic exploitation of this endogenous degradation machinery, catalyzed by pioneering studies that illuminated the potential of manipulating E3 ligases for directed protein degradation. This breakthrough was materialized in the synthesis of Protac‐1 in 2001, targeting methionyl aminopeptidase 2, thereby inaugurating a new era in targeted protein degradation (TPD) (Pasieka et al, 2023). From 2004 to 2015, a pivotal advancement was observed in the field of TPD, marked by the development of small molecules or peptides capable of recruiting the von Hippel–Lindau (VHL) ligase, alongside the innovation of novel E3 ubiquitin ligases such as MDM2, IAP, CRBN, and VHL (An & Fu, 2018).…”