Design and development of PROTACs: A new paradigm in anticancer drug discovery
Vishal Mathur, Mukund Jha, Iqra Zai, Moksh Mahajan, Shagufi Nazar, Shaheen Ali, Anam Ilyas, Sana Tanweer, Javed Ali, Ozair Alam
Abstract
• Targeted protein degradation (TPD) allows specified proteasome-mediated degradation and autophagy-mediated degradation. • PROTACs portrays good chemical and metabolic stability to degrade protein. • Exploitation of PROTAC technology as novel designed anticancer agents. • A breakthrough was attained with first PROTAC degrader targeting BRD4. • Enable us to achieve various applications in therapeutic field. PROTAC (Proteolysis targeting chimera) is a potential revolutionary strategy in cancer drug development focusing on their ability to target specific receptors like androgen and BRD4, which are vital for the progression and development of several cancers. Unlike small marketed molecule inhibitors, PROTAC function via exploiting the cells ubiquitin–proteasome system to degrade targeted protein. This innovative approach involves the usage of bifunctional small molecules that recruit an E3 ubiquitin ligase for binding to specified protein, initiating its degradation. PROTAC technique offers a unique benefit by enabling the degradation of “undruggable” proteins that are difficult to target using conventional therapies. This review elaborates the significance of PROTAC in cancer treatment and challenges involved in optimizing PROTAC design, including lowering off-target effects, enhancing pharmacokinetics, and ensuring selectivity. Despite of these problems, PROTAC based therapies displays great assurance in overcoming such as broadening spectrum of targeted proteins and drug resistance in cancers. Ultimately, PROTAC technology could transform cancer treatment via offering more personalized, precise, and effective therapeutic options, paving new ways for drug development, and providing hope for improved patient outcomes.