Recent advances of dual PROTACs for potential therapeutic applications.

Abstract

Targeted protein degradation (TPD) has revolutionized drug discovery, with PROTACs leading the charge by catalytically eliminating disease-causing proteins. While conventional PROTACs degrade a single target, the complexity of diseases like cancer and neurodegeneration-marked by redundant and compensatory signaling networks-has spurred the rapid development of dual/multi-target PROTACs capable of simultaneously degrading two or more pathogenic proteins. This review systematically surveys recent advances (2023-2026) in this area, categorizing them into two classes: those targeting homologous proteins (e.g., CDKs, BCL-2/BCL-xL, HDACs, BAZ2A/BAZ2B) and those targeting distinct proteins across interconnected pathways (e.g., ERα/ARO, α-Syn/tau, BET/HDAC, PI3K/mTOR, FLT3/CHK1, CBP/BRD4, and others). For each, we critically analyze design strategies, structure-activity relationships, linker optimization, and E3 ligase selection. Despite remarkable progress-including the first dual degraders for non-kinase epigenetic regulators and protein aggregates-challenges persist in pharmacokinetics, off-target toxicity, and limited E3 ligase diversity. By consolidating key breakthroughs and practical SAR insights, this review provides a valuable resource for advancing next-generation multi-target degraders toward clinical translation for complex diseases.