Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
Institute of Structural Biology, Rudolf Virchow Center for Integrative and Translational Bioimaging, University of Würzburg, Haus D15, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany.
Acta Crystallogr D Struct Biol. 2023 Jan 1;79(Pt 1):1-9. doi: 10.1107/S2059798322011433.
Formation of the Aurora-A-MYCN complex increases levels of the oncogenic transcription factor MYCN in neuroblastoma cells by abrogating its degradation through the ubiquitin proteasome system. While some small-molecule inhibitors of Aurora-A were shown to destabilize MYCN, clinical trials have not been satisfactory to date. MYCN itself is considered to be `undruggable' due to its large intrinsically disordered regions. Targeting the Aurora-A-MYCN complex rather than Aurora-A or MYCN alone will open new possibilities for drug development and screening campaigns. To overcome the challenges that a ternary system composed of Aurora-A, MYCN and a small molecule entails, a covalently cross-linked construct of the Aurora-A-MYCN complex was designed, expressed and characterized, thus enabling screening and design campaigns to identify selective binders.
极光激酶 A-MYCN 复合物的形成通过使致癌转录因子 MYCN 降解途径——泛素蛋白酶体系统失活，从而增加神经母细胞瘤细胞中 MYCN 的水平。虽然一些极光激酶 A 的小分子抑制剂已被证明能够使 MYCN 不稳定，但迄今为止，临床试验结果并不令人满意。由于 MYCN 本身具有较大的无规则区域，因此被认为是“不可成药”的。靶向 Aurora-A-MYCN 复合物而非单独靶向 Aurora-A 或 MYCN，将为药物开发和筛选活动开辟新的可能性。为了克服由 Aurora-A、MYCN 和小分子组成的三元系统所带来的挑战，设计、表达和表征了 Aurora-A-MYCN 复合物的共价交联构建体，从而能够进行筛选和设计活动，以鉴定选择性结合物。
