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Discovery of Nonpeptide, Reversible HER1/HER2 Dual-Targeting Small-Molecule Inhibitors as Near-Infrared Fluorescent Probes for Efficient Tumor Detection, Diagnostic Imaging, and Drug Screening.
Analytical Chemistry ( IF 6.7 ) Pub Date : 2018-12-21 00:00:00 , DOI: 10.1021/acs.analchem.8b04633 Shengnan Liu , Weijie Song , Xiangqian Gao 1 , Yanxin Su , Emily Gao 2 , Qingzhi Gao
Analytical Chemistry ( IF 6.7 ) Pub Date : 2018-12-21 00:00:00 , DOI: 10.1021/acs.analchem.8b04633 Shengnan Liu , Weijie Song , Xiangqian Gao 1 , Yanxin Su , Emily Gao 2 , Qingzhi Gao
Affiliation
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The abnormal expression of epidermal growth factor receptors HER1(EGFR) and HER2 is strongly associated with cancer invasion, metastasis, and angiogenesis. Their molecular detection is mainly executed using genetically encoded or antibody-based diagnostic tracers, but no dual-targeting small-molecule bioprobe has been achieved. Here, we report the novel small-molecule fluorescent probes Cy3-AFTN and Cy5-AFTN as potent dual-targeting inhibitors for efficient detection of HER1/HER2 expression in cancer cells and in vivo tumor diagnostic imaging. Unlike the irreversible HER1/HER2 inhibitors, Cy3-AFTN and Cy5-AFTN were designed as reversible/noncovalent probes based on the clinical drug afatinib, by making the molecule structurally impossible for receptor-mediated Michael additions. The synthesized probes were validated with live cell fluorescence imaging, flow cytometry and confocal-mediated competitive binding inhibition, molecular docking study, and in vivo xenograft tumor detection. The probes are competitively replaceable by other HER1/HER2 inhibitors; thus, they are potentially useful in fluorometric high-throughput screening for drug discovery.
中文翻译：
发现非肽，可逆HER1 / HER2双靶向小分子抑制剂作为近红外荧光探针，可用于高效肿瘤检测，诊断成像和药物筛选。
表皮生长因子受体HER1（EGFR）和HER2的异常表达与癌症的侵袭，转移和血管生成密切相关。他们的分子检测主要使用遗传编码或基于抗体的诊断示踪剂执行，但尚未实现双重目标的小分子生物探针。在这里，我们报告新型小分子荧光探针Cy3-AFTN和Cy5-AFTN作为有效的双重靶向抑制剂，可有效检测癌细胞中HER1 / HER2的表达和体内肿瘤诊断成像。与不可逆的HER1 / HER2抑制剂不同，Cy3-AFTN和Cy5-AFTN被设计为基于临床药物afatinib的可逆/非共价探针，通过使该分子在结构上无法用于受体介导的迈克尔加成。合成的探针通过活细胞荧光成像，流式细胞术和共聚焦介导的竞争性结合抑制，分子对接研究以及体内异种移植肿瘤检测进行了验证。探针可竞争性地被其他HER1 / HER2抑制剂替代；因此，它们潜在地可用于药物发现的荧光高通量筛选。
更新日期：2018-12-21
中文翻译：
发现非肽，可逆HER1 / HER2双靶向小分子抑制剂作为近红外荧光探针，可用于高效肿瘤检测，诊断成像和药物筛选。
表皮生长因子受体HER1（EGFR）和HER2的异常表达与癌症的侵袭，转移和血管生成密切相关。他们的分子检测主要使用遗传编码或基于抗体的诊断示踪剂执行，但尚未实现双重目标的小分子生物探针。在这里，我们报告新型小分子荧光探针Cy3-AFTN和Cy5-AFTN作为有效的双重靶向抑制剂，可有效检测癌细胞中HER1 / HER2的表达和体内肿瘤诊断成像。与不可逆的HER1 / HER2抑制剂不同，Cy3-AFTN和Cy5-AFTN被设计为基于临床药物afatinib的可逆/非共价探针，通过使该分子在结构上无法用于受体介导的迈克尔加成。合成的探针通过活细胞荧光成像，流式细胞术和共聚焦介导的竞争性结合抑制，分子对接研究以及体内异种移植肿瘤检测进行了验证。探针可竞争性地被其他HER1 / HER2抑制剂替代；因此，它们潜在地可用于药物发现的荧光高通量筛选。
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