ABSTRACT
Although three generations of Epidermal growth factor receptor (EGFR) - TK inhibitors have been approved for the treatment of Non-small-cell lung cancers (NSCLC), their clinical application is still largely hindered by acquired drug resistance mediated new EGFR mutations and side effects. The Proteolysis targeting chimera (PROTAC) technology has the potential to overcome acquired resistance from mutant EGFR through a novel mechanism of action. In this study, we developed the candidate degrader IV-3 by structural modifications of the lead compound 13, which exhibited limited antiproliferative activity against HCC-827 cells. Compared to compound 13, IV-3 exhibited remarkable anti-proliferative activity against HCC-827 cells, NCI-H1975 cells, and NCI-H1975-TM cells (IC50 = 0.009 µM, 0.49 µM and 3.24 µM, respectively), as well as significantly inducing degradation of EGFR protein in these cell lines (DC50 = 17.93 nM, 0.25 µM and 0.63 µM, respectively). Further investigations confirmed that IV-3 exhibited superior anti-tumor activity in all xenograft tumor models through the degradation of mutant EGFR protein. Moreover, IV-3 showed no inhibitory activity against A431 and A549 cells expressing wild-type EGFR, thereby eliminating potential toxic side effects emerging from wild-type EGFR inhibition. Overall, our study provides promising insights into EGFR-PROTACs as a potential therapeutic strategy against EGFR-acquired mutation.
Subject(s)
Antineoplastic Agents , Cell Proliferation , ErbB Receptors , Mutation , Proteolysis , ErbB Receptors/metabolism , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Cell Proliferation/drug effects , Proteolysis/drug effects , Animals , Structure-Activity Relationship , Drug Discovery , Mice , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/chemical synthesis , Drug Screening Assays, Antitumor , Molecular Structure , Cell Line, Tumor , Dose-Response Relationship, Drug , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Lung Neoplasms/metabolism , Mice, Nude , Proteolysis Targeting ChimeraABSTRACT
An efficient and scalable method for the synthesis of 3,4-dihydroisoquinolin-1(2H)-ones through benzylic oxidation of tetrahydroisoquinoline derivatives using a catalytic amount of cerium ammonium nitrate (CAN) and a stoichiometric amount of NaBrO3 as oxidants was developed. The reaction is significantly influenced by the substituent groups on the phenyl ring. While electron-withdrawing groups on the phenyl ring can lower the reactivities of the substrates, electron-donating groups on the phenyl ring can dramatically promote the oxidation rate.
