A grafted peptidomimetic for EGFR heterodimerization inhibition: Implications in NSCLC models.
A grafted peptidomimetic for EGFR heterodimerization inhibition: Implications in NSCLC models.
复制标题
EGFR异源二聚化抑制的移植肽模拟物：对NSCLC模型的影响。
DOI：
10.1016/j.ejmech.2021.113312
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发表时间：
2021-04-15
影响因子：
6.7
通讯作者：
Jois S
中科院分区：
文献类型：
--
作者：
Singh SS;Mattheolabakis G;Gu X;Withers S;Dahal A;Jois S
在肺癌中，大约85%在组织学上被分类为非小细胞肺癌（NSCLC），其是全世界癌症死亡的主要原因。已知表皮生长因子受体（EGFR）在肺癌中起关键作用。在2.4%-38%的NSCLC样本中通过免疫组织化学检测到HER 2过表达。EGFR已被三代酪氨酸激酶抑制剂（TKI）靶向，耐药性已成为一个主要问题; HER 2与EGFR的二聚化在TKI治疗耐药性的发展中也起着重要作用。我们设计了移植肽以结合HER 2细胞外结构域（ECD）并抑制EGFR：HER 2和HER 2：HER 3的蛋白质-蛋白质相互作用。向日葵胰蛋白酶抑制剂（SFTI-1）模板用于接枝拟肽化合物。在几种移植肽中，SFTI-G5在HER 2阳性NSCLC细胞系如Calu-3细胞中表现出抗增殖活性，IC 50值为0.073 μM。显示SFTI-G5结合HER 2的ECD并抑制EGFR：HER 2和HER 2：HER 3二聚化，并抑制HER 2和下游信号蛋白的磷酸化。作为概念验证，在两种NSCLC小鼠模型中评价了SFTI-G5的体内活性。SFTI-G5能够抑制两种模型中的肿瘤生长。此外，显示SFTI-G5抑制从体内模型获得的组织样品中的EGFR二聚化。这些接枝肽可用作NSCLC中EGFR二聚化的新型双重抑制剂。
Among the lung cancers, approximately 85% are histologically classified as non-small-cell lung cancer (NSCLC), a leading cause of cancer deaths worldwide. Epidermal growth factor receptors (EGFRs) are known to play a crucial role in lung cancer. HER2 overexpression is detected by immunohistochemistry in 2.4%–38% of NSCLC samples. EGFRs have been targeted with three generations of tyrosine kinase inhibitors (TKIs), and drug resistance has become a major issue; HER2 dimerization with EGFR also plays a major role in the development of resistance to TKI therapy. We have designed grafted peptides to bind to the HER2 extracellular domain (ECD) and inhibit protein-protein interactions of EGFR:HER2 and HER2:HER3. A sunflower trypsin inhibitor (SFTI-1) template was used to graft a peptidomimetic compound. Among several grafted peptides, SFTI-G5 exhibited antiproliferative activity in HER2-positive NSCLC cell lines such as Calu-3 cells with an IC50 value of 0.073 μM. SFTI-G5 was shown to bind to ECD of HER2 and inhibit EGFR:HER2 and HER2:HER3 dimerization and inhibit the phosphorylation of HER2 and downstream signaling proteins. As a proof-of-concept, the in vivo activity of SFTI-G5 was evaluated in two NSCLC mouse models. SFTI-G5 was able to inhibit tumor growth in both models. Furthermore, SFTI-G5 was shown to inhibit EGFR dimerization in tissue samples obtained from in vivo models. These grafted peptides can be used as novel dual inhibitors of EGFR dimerization in NSCLC.
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影响因子：
--
作者：
Del Re M;Rofi E;Restante G;Crucitta S;Arrigoni E;Fogli S;Di Maio M;Petrini I;Danesi R
通讯作者：
Danesi R
影响因子：
3
作者：
Kanthala S;Banappagari S;Gokhale A;Liu YY;Xin G;Zhao Y;Jois S
通讯作者：
Jois S
影响因子：
5.3
作者：
Lu, Chafen;Mi, Li-Zhi;Springer, Timothy A.
通讯作者：
Springer, Timothy A.
DOI：
10.1016/j.jtho.2015.10.025
发表时间：
2016-03
期刊：
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
影响因子：
--
作者：
Li BT;Ross DS;Aisner DL;Chaft JE;Hsu M;Kako SL;Kris MG;Varella-Garcia M;Arcila ME
通讯作者：
Arcila ME
通过药物靶向 EGFR-ERK 信号通路的数学模型预测药物组合指数并模拟网络调节动态。
影响因子：
4.6
作者：
Huang L;Jiang Y;Chen Y
通讯作者：
Chen Y