Potential applications of clickable probes in EGFR activity visualization and prediction of EGFR-TKI therapy response for NSCLC patients
Potential applications of clickable probes in EGFR activity visualization and prediction of EGFR-TKI therapy response for NSCLC patients
复制标题
可点击探针在 EGFR 活性可视化和 NSCLC 患者 EGFR-TKI 治疗反应预测中的潜在应用
DOI：
10.1016/j.ejmech.2022.114100
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发表时间：
2022-01-10
影响因子：
6.7
通讯作者：
Li, Weimin
中科院分区：
文献类型：
--
作者：
Deng, Hui;Lei, Qian;Li, Weimin
表皮生长因子受体(EGFR)在癌细胞表面异常过表达，与癌细胞的增殖、迁移、分化、凋亡和血管生成密切相关。能够以结构-功能方法可视化EGFR的工具对于预测EGFR突变和指导EGFR酪氨酸激酶抑制剂(TKI)的治疗是非常必要的。在这里，我们描述了新的、有效的和选择性的可点击探针13(HX03)、20(HX04)和24(HX05)的设计、合成和应用，通过引入炔基连接手柄来显示活的癌细胞和组织切片中的EGFR活性。这些可点击的探针是基于EGFR-TKI的关键药效团(4-苯胺喹唑啉)(例如，canertinib、dacomitinib和afatinib)的多功能化学工具，能够不可逆转地靶向EGFR的激酶结构域。其中，13个对EGFR激酶的反应活性最高，尤其是对原发突变的EGFR激酶的反应最强。使用基于活性的蛋白质谱策略，13在天然细胞环境中对内源性EGFR的标记表现出高度的敏感性和选择性。此外，13还被应用于观察非小细胞肺癌(NSCLC)移植小鼠模型和NSCLC患者肿瘤组织中EGFR突变活性，以预测EGFR-TKI的敏感性。这些结果表明，策略性设计的基于EGFR-TKI的探针可以区分人类组织中的EGFR突变，并有望成为预测EGFR-TKI治疗反应的有用诊断工具。(C)2022年爱思唯尔·马森公司。版权所有。
The epithelial growth factor receptor (EGFR) is abnormally overexpressed on the cell surface of cancer cells and is strongly associated with cancer cell proliferation, migration, differentiation, apoptosis, and angiogenesis. Tools enabling the visualization of EGFR in a structure-function approach are highly desirable to predict EGFR mutations and guide EGFR tyrosine kinase inhibitor (TKI) treatment making. Here, we describe the design, synthesis, and application of new, potent and selective clickable probes 13 (HX03), 20 (HX04) and 24 (HX05) by introducing an alkyne ligation handle to visualize EGFR activity in living cancer cells and tissue slices. These clickable probes are versatile chemical tools based on the key pharmacophore (4-anilinoquinazoline) of EGFR-TKIs (e.g., canertinib, dacomitinib and afatinib) and are able to irreversibly target the kinase domain of EGFR. Among them, 13 exhibits the highest reactivity towards EGFR kinase, particularly to EGFR kinase with primary mutations. Using activity-based protein profiling strategy, 13 showed high sensitivity and selectivity in labeling of endogenous EGFR in a native cellular context. Moreover, 13 was applied to visualize EGFR mutant activity in tumour tissues from non-small-cell lung cancer (NSCLC) xenograft mouse models, and patients with NSCLC for the prediction of EGFR-TKI sensitivity. These results demonstrate that strategically designed EGFR-TKI-based probes allow discriminating EGFR mutations in human tissues and hold promise as useful diagnostic tools in predicting EGFR-TKI therapy response. (C) 2022 Elsevier Masson SAS. All rights reserved.