The next generation of EGFR inhibitors: a patenting perspective of PROTACs based EGFR degraders

ABSTRACTIntroduction Abnormal expression of epidermal growth factor receptor (EGFR) contributes to tumor development, especially in non-small cell lung cancer (NSCLC). Although multiple inhibitors have been developed to target diverse EGFR mutations and several have been approved, the inevitable drug resistance and side effect remain a challenge, which motivates novel strategies. Proteolysis-targeting chimeras (PROTACs) have been gaining momentum for their potential as novel therapeutics for human diseases by triggering protein degradation. To date, various potent and specific EGFR PROTACs have been discovered and some of them have entered clinical trials.Areas covered This review provides an overview of EGFR degraders in patents from 2016 to 2022. It provides an update of the discovery strategies, chemical structures, and molecular profiling of all available EGFR PROTACs. SciFinder, PubMed, Web of Science, EPO, and CNIPA databases were used for searching the literature and patents for EGFR PROTACs.Expert opinion By employing the PROTAC technology, highly potent and selective EGFR degraders based on four generation EGFR inhibitors have been developed, which offer a new strategy to target EGFR mutations and overcome the drug resistance. Despite the satisfactory result in vitro and in vivo studies, their therapeutic value awaits more rigorous preclinical testing and clinical investigation.KEYWORDS: Non-small cell lung cancerEGFRPROTACsmutationprotein degradation Article highlights EGFR plays crucial roles in tumor progress and development, especially in non-small cell lung cancer.Patents in the field of EGFR PROTACs based on four generation EGFR-targeted inhibitors from 2016 to 2022 have been reviewed.EGFR PROTACs based on allosteric EGFR inhibitors exhibit potent inhibition and degradation on diverse EGFR mutants while sparing wide type EGFR.Degradation of EGFR represents a potential therapeutic strategy in EGFR-mutants resistant NSCLC patients.Declaration of interestsThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Author contribution statementZB Zheng, PY Li, BKLi, Ning Yang and TT Xu have contributed in searching and analyzing the patent literature. ZB Zheng and PY Li have designed and written the manuscript.Additional informationFundingThis paper was funded by Major New Drugs Innovation and Development [2018ZX09J18102-002].