PROTAC degraders as chemical probes for studying target biology and target validation

Abstract

This review provides guidelines for the optimization of proteolysis targeting chimeras (PROTACs) and outlines criteria for their use as chemical probes.

Targeted Protein Degradation for Infectious Diseases: from Basic Biology to Drug Discovery

“…Definitely, this article laid the foundation for an innovative PROTAC application that could lead to the development of a new class of antibacterial degraders. Besides that, the collected findings related to the structural biology of activated ClpCP support the idea that PROTACs can be used as chemical probes for basic biology or target validation endeavors …”

“…Besides that, the collected findings related to the structural biology of activated ClpCP support the idea that PROTACs can be used as chemical probes for basic biology or target validation endeavors. 78 ■ PROTACS IN PARASITIC DISEASES: DREAM OR REALITY?…”

Small-molecule PROTAC mediates targeted protein degradation to treat STAT3-dependent epithelial cancer

“…Recently, PROTAC technology has gained momentum as an effective method to induce targeted protein degradation through ubiquitination-mediated proteasomal degradation ( 47 , 48 ). The application of PROTACs has afforded several advantages for targeting STAT3 over traditional inhibitors ( 26 , 49 ).…”

Application of Novel Degraders Employing Autophagy for Expediting Medicinal Research

“…Targeted protein degradation (TPD) is a new technology for treating complex diseases that are difficult to treat using conventional medicinal treatments. − Unlike common small-molecule drug strategies, , the TPD technology enables the degradation of target proteins that serve as virtual biological signal transmission nodes for preventing and treating human diseases. ,, The TPD-based degraders enable selective degradation of target proteins that seem undruggable by engaging their biological targets in regions other than the binding pockets targeted by traditional small-molecule inhibitors. − This gives TPD-based degraders a broader range of biotargets, potency at lower dosages, and the potential to overcome drug resistance. − From the proposal of the concept of proteolysis-targeting chimera (PROTAC) to the discovery of a molecular glue that links a protein of interest (POI) to an E3 ligase or an E3 ligase complex , for degradation using the proteasomal system, the TPD technology is developing rapidly (Figure ). − This progress is represented by two PROTAC drug candidates for cancer therapy advancing into phase II clinical trials …”