Center for Biomolecular Magnetic Resonance Institute for Organic Chemistry and Chemical Biology, Johann Wolfgang Goethe University, Max-von-Laue-Straße 7, 60438, Frankfurt am Main, Germany.
Laboratory of Cellular Oncology Center for Cancer Research (CCR), National Cancer Institute (NCI), 37 Convent Drive, NIH Bethesda Campus Building 37, Room 4124, Bethesda, MD 20892, USA.
Chemistry. 2023 Apr 21;29(23):e202203967. doi: 10.1002/chem.202203967. Epub 2023 Mar 22.
The ephrin type-A receptor 2 (EPHA2) kinase belongs to the largest family of receptor tyrosine kinases. There are several indications of an involvement of EPHA2 in the development of infectious diseases and cancer. Despite pharmacological potential, EPHA2 is an under-examined target protein. In this study, we synthesized a series of derivatives of the inhibitor NVP-BHG712 and triazine-based compounds. These compounds were evaluated to determine their potential as kinase inhibitors of EPHA2, including elucidation of their binding mode (X-ray crystallography), affinity (microscale thermophoresis), and selectivity (Kinobeads assay). Eight inhibitors showed affinities in the low-nanomolar regime (K <10 nM). Testing in up to seven colon cancer cell lines that express EPHA2 reveals that several derivatives feature promising effects for the control of human colon carcinoma. Thus, we have developed a set of powerful tool compounds for fundamental new research on the interplay of EPH receptors in a cellular context.
Ephrin 型-A 受体 2 (EPHA2) 激酶属于受体酪氨酸激酶家族中最大的家族之一。有几项迹象表明 EPHA2 参与了传染病和癌症的发展。尽管具有药理学潜力，但 EPHA2 是一个研究不足的靶蛋白。在这项研究中，我们合成了一系列抑制剂 NVP-BHG712 和三嗪类化合物的衍生物。评估了这些化合物作为 EphA2 激酶抑制剂的潜力，包括阐明它们的结合模式（X 射线晶体学）、亲和力（微量热泳法）和选择性（Kinobeads 测定）。八种抑制剂表现出低纳摩尔范围内的亲和力（K <10 nM）。在表达 EphA2 的多达七种结肠癌细胞系中的测试表明，几种衍生物对控制人类结肠癌细胞具有有希望的作用。因此，我们已经开发了一组强大的工具化合物，用于在细胞环境中对 Eph 受体的相互作用进行基础性的新研究。
