PROTACs: Next-Generation Cancer Therapeutics Revolutionizing Targeted Treatment Strategies

Malignancy is a major cause of death all over the globe and leads to severe health problems. Traditional oncotherapy approaches, including surgical treatment, radiation, and chemotherapy, have been used for many years, but still have major drawbacks, like damaging healthy cells and causing severe adverse effects. In recent years, new and promising cancer medications have been developed through computer-aided drug design, immunotherapy, targeted therapies, and, in particular, a new method called PROTACs (Proteolysis Targeting Chimeras). This mode of action has two major implications. Event-based pharmacological strategies are primarily implemented with PROTACs, in which each moiety can damage the protein of interest (POI). These protein degraders, commonly known as PROTACs, have advanced rapidly in drug development. This process needs the coordinated action of three enzymes (E1, E2, and E3) and the 20S proteasome, a core component of the larger 26S proteasome complex. This review highlights that in silico computational strategies play a vital role in the rational design of PROTACs by predicting interactions among the target protein, the E3 ligase, and the Linker. Molecular docking and molecular dynamics simulations provide crucial insights into the stability and dynamics of the ternary complex. AI-based ternary prediction, linker optimization, AI-ML generative linker design, and AI-enhanced ADMET models are helpful in the design of multitarget PROTACs. PROTACs targeting oncoproteins include BRD4, BTK, ALK, AR, and CDK9. Over the past ten years, many preclinical and clinical PROTACs have been in the drug discovery pipeline, which include ARV-771, ARV-825, MS154, YX-2-107, BSJ-02-162, CP5V, dBRD9, ERD-308, ARV-110, ARV-766, ARV-471, KT-474, PF-06550833, and NX-5948. From clinical and preclinical trials, PROTACs suggest that this approach is an important tool in oncotherapy. The introduction of PROTACs is a huge step in current oncotherapy, as they are no longer conventional inhibitors but instead induce degradation of the target protein. These computational approaches significantly reduce the experimental workload and accelerate the design and development of novel multi-target PROTACs. PROTAC technology offers several opportunities but also poses serious challenges for the next generation of oncotherapy.