Abstract & Overview
Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, with treatment challenges arising from late-stage diagnosis, therapy resistance, and the presence of undruggable targets. The advent of proteolysis-targeting chimeras (PROTACs) offers a novel therapeutic avenue by leveraging the ubiquitin-proteasome system (UPS) for targeted protein degradation. Unlike conventional inhibitors that act like temporary “off switches” for cancer-related proteins, PROTACs function as “disposal tags,” marking harmful proteins for complete removal by the cell, enabling sustained oncogenic protein degradation. PROTACs address key drivers of CRC progression, including Kirsten rat sarcoma viral oncogene homolog (KRAS) , the Wnt/β-catenin pathway, bromodomain-containing protein 4 (BRD4), cyclin-dependent kinase 4/6 (CDK4/6), signal transducer and activator of transcription 3 (STAT3), and DNA repair regulators. This review explores the mechanistic foundation of PROTACs, their application in CRC therapy, and the ongoing advancements in optimizing their selectivity, bioavailability, and clinical translation. While challenges such as E3 ligase selection, intracellular delivery, and resistance mechanisms remain, recent innovations in linker chemistry, nanocarrier systems, and artificial intelligence (AI)-driven drug design are enhancing the clinical feasibility of PROTAC therapeutics. As research progresses, PROTAC-based therapies hold significant promise for overcoming current treatment limitations, paving the way for a new era of precision medicine in CRC management.