Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, P. R. China.
Department of Medical Oncology, Shaanxi Provincial People's Hospital, Xi'an 710068, Shaanxi, P. R. China.
J Med Chem. 2022 Mar 24;65(6):4709-4726. doi: 10.1021/acs.jmedchem.1c01827. Epub 2022 Mar 7.
Drug resistance caused by epidermal growth factor receptor (EGFR) mutation has largely limited the clinical use of EGFR tyrosine kinase inhibitors (EGFR-TKIs) for the treatment of non-small-cell lung cancer (NSCLC). Herein, to overcome the intractable problem of drug resistance, proteolysis targeting chimeras (PROTACs) targeting EGFR mutants were developed by optimizing covalent EGFR ligands. Covalent or reversible covalent pyrimidine- or purine-containing PROTACs were designed, synthesized, and evaluated. As a consequence, covalent PROTAC , with a novel purine-containing EGFR ligand, was discovered as a highly potent degrader against EGFR and EGFR, reaching the lowest DC values among all reported EGFR-targeting PROTACs. Furthermore, exhibited excellent cellular activity against the H1975 and HCC827 cell lines with high selectivity. Mechanism investigation indicated that the lysosome was involved in the degradation process. Importantly, the covalent binding strategy was proven to be an effective approach for the design of PROTACs targeting EGFR, which laid the practical foundation for further development of potent EGFR-targeting PROTACs.
表皮生长因子受体（EGFR）突变引起的耐药性在很大程度上限制了 EGFR 酪氨酸激酶抑制剂（EGFR-TKIs）在非小细胞肺癌（NSCLC）治疗中的临床应用。在此，为了克服耐药性这一难题，通过优化共价 EGFR 配体，开发了针对 EGFR 突变体的蛋白酶体靶向嵌合体（PROTACs）。设计、合成并评价了含有共价或可逆共价嘧啶或嘌呤的 PROTACs。结果发现，新型嘌呤类 EGFR 配体的共价 PROTAC 对 EGFR 和 EGFR 具有很高的降解活性，达到了所有报道的 EGFR 靶向 PROTAC 中最低的 DC 值。此外，对高选择性的 H1975 和 HCC827 细胞系表现出优异的细胞活性。机制研究表明，溶酶体参与了降解过程。重要的是，共价结合策略被证明是设计针对 EGFR 的 PROTAC 的有效方法，为进一步开发有效的 EGFR 靶向 PROTAC 奠定了实践基础。
