Ankush Kumar, Vishakha Sharma, Pallvi Kumari, Rajwinder Kaur, Rohit Bhatia
The development of epidermal growth factor receptor (EGFR) C797S/L858R/T790M mutation has become a major barrier to tyrosine kinase inhibitors (TKIs). These mutations reduce the drug binding and increase the adenosine triphosphate (ATP) competition, which continues the EGFR signaling. As C797S/L858R/T790M resistance rates continue to rise, there is an urgent need for therapeutic strategies that are capable of eliminating the wild type and mutated forms of EGFR. Proteolysis-targeting chimera (PROTAC)-based degraders have recently gained significant attention as next-generation targeted degradation rather than simply enzymatic inhibition. PROTACs work through protein degradation and can bypass the many limitations of classical inhibitors. Recent studies from 2020-2025 have reported many EGFR-directed PROTACs for such mutations. Several of these degraders showed excellent activity against C797S as well as L858R and T790M. In this review, the authors have compiled the PROTACs designed in this duration. The authors have also discussed their medicinal chemistry, structure-activity relationship (SAR), and key features that could improve the binding and degradation efficiency. Overall, this review provides an updated overview of next-generation EGFR degraders and their potential to overcome the C797S/L858R/T790M-mediated drug resistance.