Chemistry-Driven Integrated Innovation: Unleashing the Potential of PROTAC Technology

Abstract Proteolysis-targeting chimeras (PROTACs) are driving medicinal chemistry progress, yet efficient synthesis and rational linker design remain two critical bottlenecks for their clinical translation. Those core challenges directly limit the advancement of PROTACs from preclinical research to practical application. This review focuses on state-of-the-art enabling chemical strategies to address these key bottlenecks, ensuring tight relevance to PROTACs development needs. The modular assembly can be streamlined by click chemistry, multicomponent, and late-stage C–H functionalizations, whereas microscale and solid-phase platforms can be used to deliver thousands of analogues in days without purification. In this work, we emphasize covalent sulfonyl fluoride warheads and photocaged or photoswitchable scaffolds that provide spatiotemporal control of degradation. The employment of dynamic combinatorial chemistry, DNA-encoded libraries, and intracellular self-assembly further expands chemical space and accelerates hit triage. At last, we outline how artificial intelligence-driven modeling integrates these data to predict linker length, exit vector geometry, and ADME profiles, shortening iterative design cycles. Collectively, these chemistry-centric innovations are turning PROTACs from a conceptual breakthrough into a practical drug-discovery engine by directly addressing the synthesis, optimization, and functional control challenges that have impeded their clinical advancement.