College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea.
J Enzyme Inhib Med Chem. 2020 Dec;35(1):1822-1833. doi: 10.1080/14756366.2020.1825407.
The TAM (Axl, Mer, and Tyro3) family is implicated in the survival and chemoresistance of tumours and has emerged as a potential therapeutic target. A novel series of 7-aryl-2-anilino-pyrrolopyrimidines were identified as potent Axl/Mer tyrosine kinase inhibitors without significant inhibition of Tyro3. A representative compound exhibited IC values of 2 nM and 16 nM for Mer and Axl, respectively, and considerable inhibition for Mer phosphorylation in cells. Docking studies suggested that the formation of a salt bridge between the nitrogen of the aniline moiety with ASP678 of the Mer kinase domain as well as an interaction with the hinge region that most kinase inhibitors have in common would be essential to retain activity. These results could provide useful information for finding promising inhibitors of Axl/Mer for the treatment of cancer.
TAM（Axl、Mer 和 Tyro3）家族与肿瘤的存活和化疗耐药性有关，已成为潜在的治疗靶点。我们发现了一系列新型的 7-芳基-2-苯胺基吡咯嘧啶，它们可强效抑制 Axl/Mer 酪氨酸激酶，而对 Tyro3 的抑制作用不明显。代表性化合物在细胞中对 Mer 和 Axl 的 IC 值分别为 2 nM 和 16 nM，对 Mer 磷酸化有显著抑制作用。对接研究表明，苯胺部分的氮与 Mer 激酶结构域的 ASP678 形成盐桥，以及与 hinge 区域相互作用（这是大多数激酶抑制剂共有的）对保留活性至关重要。这些结果为寻找有前途的 Axl/Mer 抑制剂治疗癌症提供了有用的信息。
