Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou 310018, PR China.
Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou 310018, PR China.
Bioorg Chem. 2024 Jun;147:107394. doi: 10.1016/j.bioorg.2024.107394. Epub 2024 Apr 26.
Epidermal growth factor receptor (EGFR) is one of the most studied drug targets for treating non-small-cell lung cancer (NSCLC). However, there are no approved inhibitors for the C797S resistance mutation caused by the third-generation EGFR inhibitor (Osimertinib). Therefore, the development of fourth-generation EGFR inhibitors is urgent. In this study, we clarified the structure-activity relationship of several synthesized compounds as fourth-generation inhibitors against human triple (Del19/T790M/C797S) mutation. Representative compound 52 showed potent inhibitory activity against EGFR with an IC of 0.55 nM and significantly inhibited the proliferation of the Ba/F3 cell line harboring EGFR with an IC of 43.28 nM. Moreover, 52 demonstrated good pharmacokinetic properties and excellent in vivo efficacy. Overall, the compound 52 can be considered a promising candidate for overcoming EGFR C797S-mediated mutations.
表皮生长因子受体 (EGFR) 是治疗非小细胞肺癌 (NSCLC) 的最受关注的药物靶点之一。然而，对于第三代 EGFR 抑制剂（奥希替尼）引起的 C797S 耐药突变，目前尚无批准的抑制剂。因此，开发第四代 EGFR 抑制剂迫在眉睫。在这项研究中，我们阐明了几种合成化合物作为针对人类三重（Del19/T790M/C797S）突变的第四代抑制剂的结构-活性关系。代表性化合物 52 对 EGFR 的抑制活性很强，IC 为 0.55 nM，对携带 EGFR 的 Ba/F3 细胞系的增殖抑制作用显著，IC 为 43.28 nM。此外，52 还表现出良好的药代动力学特性和优异的体内疗效。总体而言，化合物 52 可被视为克服 EGFR C797S 介导的突变的有前途的候选药物。
