2. Academic Validation
  3. Structure optimization and discovery of novel compound for the treatment of insertion mutations within exon 20 of EGFR and HER2

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

  • Bioorg Med Chem. 2023 Mar 1:81:117202. doi: 10.1016/j.bmc.2023.117202.
Yetong Cui 1,  Ruonan Wang 1,  Yujiao Wei 1,  Fei Hou 1,  Haixi Li 1,  Yurui Jiang 1,  Yue Sun 1,  Shushu Fu 2,  Lina Zuo 2,  Xiaoji Wang 3,  Ming Li 4,  Jinling Li 5,  Ning Liu 6,  Kun Zhang 7,  Mingming Wei 8,  Guang Yang 9
Affiliations

Affiliations

  • 1 The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, PR China.
  • 2 Engineering Research Center of Health Food Design & Nutrition Regulation, School of Chemical Engineering and Energy Technology, Dongguan University of Technology, Dongguan, 523808 Guangdong Province, PR China.
  • 3 Engineering Research Center of Health Food Design & Nutrition Regulation, School of Chemical Engineering and Energy Technology, Dongguan University of Technology, Dongguan, 523808 Guangdong Province, PR China. Electronic address: wangxj@dgut.edu.cn.
  • 4 Cangzhou Institutes for Food and Drug Control, Cangzhou, 061000 Hebei Province, PR China. Electronic address: 83991223@qq.com.
  • 5 Kangtai Pharmceutical Co. Ltd of Hebei, Cangzhou, 061000 Hebei Province, PR China. Electronic address: jinoplk@qq.com.
  • 6 The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, PR China. Electronic address: liuning@nankai.edu.cn.
  • 7 The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, PR China. Electronic address: zhangkun1112@163.com.
  • 8 The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, PR China. Electronic address: mingmingshengwu@163.com.
  • 9 The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, PR China. Electronic address: guang.yang@nankai.edu.cn.
PMID: 36804726 DOI: 10.1016/j.bmc.2023.117202
Abstract

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.

Keywords

Exon 20 of EGFR and HER2; Molecular hybridization; Non-small cell lung cancer; Tyrosine kinase inhibitors.

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