Next-generation cancer therapeutics: PROTACs and the role of heterocyclic warheads in targeting resistance

Abstract

One of the major obstacles to sustained cancer treatment effectiveness is the development of medication resistance. Current therapies that block proteins associated with cancer progression often lose their efficacy due to acquired drug resistance, which is frequently driven by mutated or overexpressed protein targets. Proteolysis-targeting chimeras (PROTACs) offer an alternative therapeutic strategy by hijacking the cell's ubiquitin-proteasome system to degrade disease-causing proteins, presenting several potential advantages. Over the past few years, PROTACs have been developed to target various cancer-related proteins, offering new treatment options for patients with previously untreatable malignancies and serving as a foundation for next-generation therapeutics. One of the notable benefits of PROTACs is their ability to overcome certain resistance mechanisms that limit the effectiveness of conventional targeted therapies, as shown in several recent studies. Additionally, research teams are investigating how PROTACs can selectively degrade mutant proteins responsible for resistance to first-line cancer therapies. In the pursuit of novel and effective treatments, this review highlights recent advancements in the development of PROTACs aimed at overcoming cancer resistance. When it comes to drug design, heterocyclic scaffolds often serve as a foundational framework, offering opportunities for modification and optimization of novel molecules. Researchers are similarly exploring various heterocyclic derivatives as “warheads” in the design of PROTACs has been instrumental in pushing the boundaries of targeted protein degradation. As warheads, these heterocyclic compounds are responsible for recognizing and binding to the target protein, which ultimately leads to its degradation via the ubiquitin-proteasome system. This study aims to provide a comprehensive overview of cutting-edge strategies in PROTAC design, offering detailed insights into key concepts and methodologies for creating effective PROTACs. Special emphasis is placed on structure-based rational design, the development of novel warheads, and their critical in influencing biological activity.