Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig, Beethovenstraße 55, 38106 Braunschweig, Germany.
Zentrum für Pharmaverfahrenstechnik (PVZ), Technische Universität Braunschweig, Franz-Liszt-Straße 35A, 38106 Braunschweig, Germany.
Molecules. 2021 Mar 14;26(6):1611. doi: 10.3390/molecules26061611.
Although overexpression and hyperactivity of protein kinases are causative for a wide range of human cancers, protein kinase inhibitors currently approved as cancer drugs address only a limited number of these enzymes. To identify new chemotypes addressing alternative protein kinases, the basic structure of a known PLK1/VEGF-R2 inhibitor class was formally dissected and reassembled. The resulting 7-(2-anilinopyrimidin-4-yl)-1-benzazepin-2-ones were synthesized and proved to be dual inhibitors of Aurora A kinase and VEGF receptor kinases. Crystal structures of two representatives of the new chemotype in complex with Aurora A showed the ligand orientation in the ATP binding pocket and provided the basis for rational structural modifications. Congeners with attached sulfamide substituents retained Aurora A inhibitory activity. In vitro screening of two members of the new kinase inhibitor family against the cancer cell line panel of the National Cancer Institute (NCI) showed antiproliferative activity in the single-digit micromolar concentration range in the majority of the cell lines.
尽管蛋白激酶的过度表达和异常激活与多种人类癌症有关，但目前被批准用于癌症治疗的蛋白激酶抑制剂仅能针对其中少数几种酶。为了寻找针对其他蛋白激酶的新化学类型，我们对一种已知的 PLK1/VEGF-R2 抑制剂结构进行了正式的剖析和重组。由此得到的 7-(2-苯胺嘧啶-4-基)-1-苯并氮杂卓-2-酮类化合物被合成出来，并被证明是 Aurora A 激酶和 VEGF 受体激酶的双重抑制剂。两个新型化学类型化合物与 Aurora A 的复合物的晶体结构显示了配体在 ATP 结合口袋中的取向，并为合理的结构修饰提供了依据。带有磺酰胺取代基的类似物保留了对 Aurora A 的抑制活性。对新的激酶抑制剂家族的两个成员在国立癌症研究所（NCI）的癌细胞系筛选中显示，在大多数细胞系中，它们在十位数微摩尔浓度范围内具有抗增殖活性。
