Advances in the Application of PROTAC Technology in Cancer Therapy
TL;DR
Optimized ligand-linker design, tumor-selective E3 ligases, prodrug strategies and biomarker-guided clinical trials are expected to greatly promote the clinical development of PROTAC-based anticancer therapies.
Abstract
Traditional small-molecule anticancer inhibitors primarily block single protein activities and are vulnerable to mutation-mediated drug resistance. Proteolysis-targeting chimera (PROTAC) technology induces the ubiquitin-proteasome-dependent clearance of oncogenic proteins and provides a promising new strategy for precision cancer therapy. This paper summarizes the molecular basis, degradation mechanism, design principles, and translational progress of PROTAC degraders in cancer treatment. PROTACs consist of a target ligand, an E3 ubiquitin ligase ligand and a connecting linker, and they exert unique event-driven antitumor effects by inducing ternary complex formation and target ubiquitination. Representative ER, AR, BTK, BCL-xL, and BRD4 degraders have shown promising preclinical or clinical activity, especially in drug-resistant tumors. Current challenges include poor oral pharmacokinetic properties, incomplete tumor selectivity, uncertain long-term safety, and emerging resistance mechanisms related to ubiquitin signaling. Optimized ligand-linker design, tumor-selective E3 ligases, prodrug strategies and biomarker-guided clinical trials are expected to greatly promote the clinical development of PROTAC-based anticancer therapies.