Chemveda Life Sciences India Pvt. Ltd., #B-11/1, IDA Uppal, Hyderabad 500039, Telangana, India; Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad 500 085, Telangana, India.
Department of Chemistry, Osmania University, Hyderabad 500007, Telangana, India.
Bioorg Med Chem. 2021 Feb 1;31:115962. doi: 10.1016/j.bmc.2020.115962. Epub 2020 Dec 31.
We describe in this paper the synthesis of a novel series of anilino-2-quinazoline derivatives. These compounds have been screened against a panel of eight mammalian kinases and in parallel they were tested for cytotoxicity on a representative panel of seven cancer cell lines. One of them (DB18) has been found to be a very potent inhibitor of human "CDC2-like kinases" CLK1, CLK2 and CLK4, with IC values in the 10-30 nM range. Interestingly, this molecule is inactive at 100 μM on the closely related "dual-specificity tyrosine-regulated kinase 1A" (DYRK1A). Extensive molecular simulation studies have been performed on the relevant kinases to explain the strong affinity of this molecule on CLKs, as well as its selectivity against DYRK1A.
本文介绍了一系列新型苯胺-2-喹唑啉衍生物的合成。这些化合物已针对一组八种哺乳动物激酶进行了筛选，同时还针对七种代表性癌细胞系进行了细胞毒性测试。其中一种（DB18）被发现是人类“CDC2 样激酶”CLK1、CLK2 和 CLK4 的非常有效的抑制剂，IC 值在 10-30 nM 范围内。有趣的是，这种分子在 100 μM 时对密切相关的“双特异性酪氨酸调节激酶 1A”（DYRK1A）没有活性。已经对相关激酶进行了广泛的分子模拟研究，以解释该分子对 CLKs 的强亲和力以及对 DYRK1A 的选择性。
