A peptidomimetic with a chiral switch is an inhibitor of epidermal growth factor receptor heterodimerization.
A peptidomimetic with a chiral switch is an inhibitor of epidermal growth factor receptor heterodimerization.
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DOI：
10.18632/oncotarget.19013
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发表时间：
2017-09-26
期刊：
影响因子：
--
通讯作者：
Jois SD
中科院分区：
文献类型：
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作者：
Kanthala SP;Liu YY;Singh S;Sable R;Pallerla S;Jois SD
在不同类型的EGFR二聚体中，EGFR- her2和HER2-HER3在不同类型的癌症中是众所周知的。靶向EGFR二聚化将对癌症治疗产生重大影响。设计了一种对称的拟肽来抑制EGFR的蛋白-蛋白相互作用。模拟肽(Cyclo（1,10)PpR (R) Anapa-FDDF-(R)- anapa)R，化合物18）在表达her2的乳腺癌细胞系和肺癌细胞系中显示出抗增殖活性，IC50为194 nM。该拟肽在结构上具有一个Pro-Pro序列以稳定β-旋向和一个β-氨基酸，即氨基萘基丙酸。为了研究β-氨基酸的手性对肽结构及其抗增殖活性的影响，设计并合成了化合物18的非对映异构体。这些化合物的构效关系表明，所设计的化合物在β-氨基酸上存在一个手性开关。在β-氨基酸上具有R构型和L-Pro-D-Pro序列的拟肽是最具活性的化合物（18）。通过酶补体碎片化实验和接近连接实验，我们发现化合物18抑制HER2:HER3和EGFR:HER2二聚体。表面等离子体共振研究表明，化合物18与HER2细胞外结构域结合，特别是与结构域IV结合。利用小鼠乳腺癌异种移植模型评估了化合物18的抗癌活性；与对照组相比，化合物18抑制了小鼠的肿瘤生长。化合物18也被证明与厄洛替尼对EGFR突变的肺癌细胞系具有协同作用。
Among different types of EGFR dimers, EGFR-HER2 and HER2-HER3 are well known in different types of cancers. Targeting dimerization of EGFR will have a significant impact on cancer therapies. A symmetric peptidomimetic was designed to inhibit the protein-protein interaction of EGFR. The peptidomimetic (Cyclo(1,10)PpR (R) Anapa-FDDF-(R)-Anapa)R, compound 18) was shown to exhibit antiproliferative activity with an IC50 of 194 nM in HER2-expressing breast cancer cell lines and 18 nM in lung cancer cell lines. The peptidomimetic has a Pro-Pro sequence in the structure to stabilize the β-turn and a β-amino acid, amino napthyl propionic acid. To investigate the effect of the chirality of β-amino acid on the structure of the peptide and its antiproliferative activity, diastereoisomers of compound 18 were designed and synthesized. Structure-activity relationships of these compounds indicated that there is a chiral switch at β-amino acid in the designed compound. The peptidomimetic with R configuration at β-amino acid and with a L-Pro-D-Pro sequence was the most active compound (18). Using enzyme complement fragmentation assay and proximity ligation assay, we show that compound 18 inhibits HER2:HER3 and EGFR:HER2 dimerization. Surface plasmon resonance studies suggested that compound 18 binds to the HER2 extracellular domain and in particular to domain IV. The anticancer activity of compound 18 was evaluated using a xenograft model of breast cancer in mice; compound 18 suppressed the tumor growth in mice compared to control. Compound 18 was also shown to have a synergistic effect with erlotinib on EGFR mutated lung cancer cell lines.