Naik Himgauri, Gauthier Ted, Singh Sitanshu, Jois Seetharama
School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, United States.
Biotechnology Laboratory, LSU AgCenter, Louisiana State University, Baton Rouge, LA 70803, United States.
Bioorg Med Chem Lett. 2018 Dec 1;28(22):3506-3513. doi: 10.1016/j.bmcl.2018.10.005. Epub 2018 Oct 3.
The human epidermal growth factor receptor (EGFR) family is known to be involved in cell signaling pathways. The extracellular domain of EGFR consists of four domains, of which domain II and domain IV are known to be involved in the dimerization process. Overexpression of these receptors is known to play a significant role in heterodimerization of these receptors leading to the development of cancer. We have designed peptidomimetic molecules to inhibit the EGFR heterodimerization interaction that have shown antiproliferative activity and specificity for HER2-positive cancer cell lines. Among these, a peptidomimetic, compound 5, exhibited antiproliferative activity at low nanomolar concentrations in HER2-overexpressing cancer cell lines. To improve the stability of this peptidomimetic, we have designed and synthesized a novel conjugate of peptidomimetic compound 5 with a lipid, stearic acid. The antiproliferative activity of this conjugate was evaluated in HER2-positive cancer cell lines. Results suggested that the conjugate exhibited selective antiproliferative activity in HER2-overexpressing breast and lung cancer cell lines and was able to block HER2:HER3 heterodimerization. Also, the conjugate showed improved stability with a half-life of 5 h in human serum compared to the half-life of 2 h for parent compound 5. The binding affinity of the conjugate to HER2 protein was evaluated by SPR analysis, and the mode of binding of the lipid conjugate to domain IV of HER2 protein was demonstrated by docking analysis. Thus, this novel lipid conjugate can be used to target HER2-overexpressing cancers.
已知人类表皮生长因子受体（EGFR）家族参与细胞信号通路。EGFR的细胞外结构域由四个结构域组成，其中结构域II和结构域IV已知参与二聚化过程。已知这些受体的过表达在这些受体的异源二聚化中起重要作用，导致癌症的发生。我们设计了拟肽分子来抑制EGFR异源二聚化相互作用，这些分子已显示出对HER2阳性癌细胞系的抗增殖活性和特异性。其中，一种拟肽化合物5在HER2过表达的癌细胞系中，在低纳摩尔浓度下表现出抗增殖活性。为了提高这种拟肽的稳定性，我们设计并合成了一种拟肽化合物5与硬脂酸的新型脂质缀合物。在HER2阳性癌细胞系中评估了这种缀合物的抗增殖活性。结果表明，该缀合物在HER2过表达的乳腺癌和肺癌细胞系中表现出选择性抗增殖活性，并且能够阻断HER2:HER3异源二聚化。此外，与母体化合物5的2小时半衰期相比，该缀合物在人血清中的半衰期为5小时，稳定性有所提高。通过SPR分析评估了缀合物与HER2蛋白的结合亲和力，并通过对接分析证明了脂质缀合物与HER2蛋白结构域IV的结合模式。因此，这种新型脂质缀合物可用于靶向HER2过表达的癌症。
