Center for Biomaterials, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul, 130-650, Republic of Korea; Department of Biomolecular Science, Korea University of Science and Technology, 113 Gwahangno, Yuseong-gu, Daejeon, 305-333, Republic of Korea.
Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates.
Eur J Med Chem. 2021 Nov 15;224:113674. doi: 10.1016/j.ejmech.2021.113674. Epub 2021 Jun 29.
This article reports on novel imidazothiazole derivatives as first-in-class potent and selective ErbB4 (HER4) inhibitors. There are no other reported selective inhibitors of this kinase in the literature, that's why they are considered as first-in-class. In addition, none of the reported non-selective ErbB4 inhibitors possesses imidazothiazole nucleus in its structure. Therefore, there is novelty in this work in both kinase selectivity and chemical structure. Compounds Ik and IIa are the most potent ErbB4 kinase inhibitor (IC = 15.24 and 17.70 nM, respectively). Compound Ik showed promising antiproliferative activity. It is selective towards cancer cell lines than normal cells. Its ability to penetrate T-47D cell membrane and inhibit ErbB4 kinase inside the cells has been confirmed. Moreover, both compound Ik and IIa have additional merits such as weak potency against hERG ion channels and against CYP 3A4 and 2D6. Molecular docking and dynamic simulation studies were carried out to explain binding interactions.
这篇文章报道了新型咪唑并噻唑衍生物作为一类新型强效和选择性 ErbB4（HER4）抑制剂。目前文献中尚无其他报道的这种激酶的选择性抑制剂，这就是为什么它们被认为是一类新型抑制剂。此外，在文献报道的非选择性 ErbB4 抑制剂中，没有一种具有咪唑并噻唑核结构。因此，这项工作在激酶选择性和化学结构两方面都具有新颖性。化合物 Ik 和 IIa 是最有效的 ErbB4 激酶抑制剂（IC50 分别为 15.24 和 17.70 nM）。化合物 Ik 表现出有希望的抗增殖活性。它对癌细胞系比对正常细胞更具选择性。已经证实它能够穿透 T-47D 细胞膜并在细胞内抑制 ErbB4 激酶。此外，化合物 Ik 和 IIa 还有其他优点，例如对 hERG 离子通道和 CYP 3A4 和 2D6 的抑制作用较弱。进行了分子对接和动态模拟研究以解释结合相互作用。
