Structure optimization and discovery of novel compound for the treatment of insertion mutations within exon 20 of EGFR and HER2

• Published in: Bioorganic & medicinal chemistry 2023-03, Vol.81, p.117202-117202, Article 117202
• Main Authors: Cui, Yetong, Wang, Ruonan, Wei, Yujiao, Hou, Fei, Li, Haixi, Jiang, Yurui, Sun, Yue, Fu, Shushu, Zuo, Lina, Wang, Xiaoji, Li, Ming, Li, Jinling, Liu, Ning, Zhang, Kun, Wei, Mingming, Yang, Guang
• Format: Article
• Language: English
• Subjects: Carcinoma, Non-Small-Cell Lung - drug therapy; ErbB Receptors; Exon 20 of EGFR and HER2; Exons; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Molecular hybridization; Mutagenesis, Insertional; Mutation; Non-small cell lung cancer; Protein Kinase Inhibitors - chemistry; Tyrosine kinase inhibitors
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2023.117202

[Display omitted] •25 novel Afatinib-Poziotinib hybrids were designed via 3D modeling of kinase structure.•Compound 56 could inhibit the growth of tumor cells with various HER2 exon 20 mutations and EGFR mutants both in vitro and in vivo.•Compound 56 could remarkably reduced binding affinity with hERG protein. In previous decades, patients with the most active EGFR mutations in non-small cell lung cancer (NSCLC) have significantly benefited from EGFR tyrosine kinase inhibitors (TKIs). However, a minority with EGFR and HER2 exon 20 mutations are inherently resistant to treatment. Several molecular TKIs (such as TAK788 and Poziotinib) were recently discovered and demonstrated as effective inhibitors against the most prevalent HER2 or EGFR exon 20 mutations. However, low clinical efficiency and uncertain adverse reaction indicated that the development of effective therapies is still demanded. In the present work, we designed several hybrid compounds learning from 3D modeling of kinase structure. One lead compound (compound 56) was found to be the most potent compound with IC50 value of 0.027 nM against EGFR D770-N771 ins NPG and reduced binding affinity with hERG protein. In vitro and in vivo biological results suggested that compound 56 demonstrated good oral bioavailability, and it was significantly capable of inhibiting the growth of tumor cells with a variety of HER2 exon 20 mutations and EGFR mutants with negligible toxic effects. It was identified that compound 56 might be considered a potential drug candidate for NSCLC target therapy.