Elkamhawy Ahmed, Son Seohyun, Lee Hwa Young, El-Maghrabey Mahmoud H, Hamd Mohamed A El, Alshammari Saud O, Abdelhameed Abeer A, Alshammari Qamar A, Abdeen Ahmed, Ibrahim Samah F, Mahdi Wael A, Alshehri Sultan, Alnajjar Radwan, Choi Won Jun, Al-Karmalawy Ahmed A, Lee Kyeong
BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Republic of Korea.
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
Pharmaceuticals (Basel). 2022 Dec 28;16(1):43. doi: 10.3390/ph16010043.
Co-expression of the epidermal growth factor receptor (EGFR, also known as ErbB1) and human epidermal growth factor receptor 2 (HER2) has been identified as a diagnostic or prognostic sign in various tumors. Despite the fact that lapatinib (EGFR/HER2 dual inhibitor) has shown to be successful, many patients do not respond to it or develop resistance for a variety of reasons that are still unclear. As a result, new approaches and inhibitory small molecules are still needed for EGFR/HER2 inhibition. Herein, novel lapatinib derivatives possessing 4-anilinoquinazoline and imidazole scaffolds (-) were developed and screened as EGFR/HER2 dual inhibitors. In vitro and in silico investigations revealed that compound has a high affinity for the ATP-binding regions of EGFR and HER2. All of the designed candidates were predicted to not penetrate the BBB, raising the expectation for the absence of CNS side effects. At 10 µM, derivatives possessing 3-chloro-4-(pyridin-2-ylmethoxy)aniline moiety (-) demonstrated outstanding ranges of percentage inhibition against EGFR (97.65-99.03%) and HER2 (87.16-96.73%). Compound showed nanomolar IC values over both kinases (1.8 nM over EGFR and 87.8 nM over HER2). Over EGFR, compound was found to be 50-fold more potent than staurosporine and 6-fold more potent than lapatinib. A kinase selectivity panel of compound showed poor to weak inhibitory activity over CDK2/cyclin A, c-MET, FGFR1, KDR/VEGFR2, and P38a/MAPK14, respectively. Structure-activity relationship (SAR) that were obtained with different substitutions were justified. Additionally, molecular docking and molecular dynamics studies revealed insights into the binding mode of the target compounds. Thus, compound was identified as a highly effective and dual EGFR/HER2 inhibitor worthy of further investigation.
表皮生长因子受体（EGFR，也称为ErbB1）和人表皮生长因子受体2（HER2）的共表达已被确定为多种肿瘤的诊断或预后指标。尽管拉帕替尼（EGFR/HER2双重抑制剂）已被证明是成功的，但许多患者由于各种尚不清楚的原因对其没有反应或产生耐药性。因此，仍然需要新的方法和抑制性小分子来抑制EGFR/HER2。在此，开发并筛选了具有4-苯胺基喹唑啉和咪唑支架的新型拉帕替尼衍生物（-）作为EGFR/HER2双重抑制剂。体外和计算机模拟研究表明，化合物对EGFR和HER2的ATP结合区域具有高亲和力。所有设计的候选物预计都不会穿透血脑屏障，这增加了对无中枢神经系统副作用的期望。在10μM时，具有3-氯-4-（吡啶-2-基甲氧基）苯胺部分的衍生物（-）对EGFR（97.65-99.03%）和HER2（87.16-96.73%）表现出出色的抑制百分比范围。化合物对两种激酶均显示出纳摩尔IC值（对EGFR为1.8 nM，对HER2为87.8 nM）。在EGFR上，发现化合物比星形孢菌素强50倍，比拉帕替尼强6倍。化合物的激酶选择性面板分别对CDK2/细胞周期蛋白A、c-MET、FGFR1、KDR/VEGFR2和P38a/MAPK14显示出弱至中等的抑制活性。对不同取代获得的构效关系（SAR）进行了验证。此外，分子对接和分子动力学研究揭示了目标化合物结合模式的见解。因此，化合物被确定为一种值得进一步研究的高效双EGFR/HER2抑制剂。
