Ibrahim Tamer M, Ernst Christoph, Lange Andreas, Hennig Susanne, Boeckler Frank M
Laboratory for Molecular Design and Pharmaceutical Biophysics, Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Eberhard Karls University Tübingen, Tübingen, Germany.
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Kafrelsheikh University, Kafr El-Sheikh, Egypt.
Drug Des Devel Ther. 2019 Dec 18;13:4247-4263. doi: 10.2147/DDDT.S224561. eCollection 2019.
Survivin is a nodal protein involved in several cellular pathways. It is a member of the IAP family and an integral component of the chromosomal passenger complex, where it binds to borealin and INCENP through its dimerization interface. By targeting survivin with a small molecule at its dimerization interface, inhibition of the proliferation of cancer cells has been suggested. With Abbott 8, a small-molecule dimerization inhibitor has been recently reported. The structure-activity relationship of this series of inhibitors implied that the middle pyridin-2(1)-one ring did not tolerate modifications of any kind.
Based on the synthetic strategy of Abbott 8 using multicomponent reactions, we synthesized a series of small molecules bearing a novel rigidized core scaffold. This rigidization strategy was accomplished by integrating the pyridin-2(1)-one and its 6-phenyl substituent into a tricyclic structure, linking position 5 of pyridin-2(1)-one to the phenyl substituent by rings of different sizes. The new scaffolds were designed based on in silico molecular dynamics of survivin.
Binding of these rigidized scaffolds to the recombinant L54M mutant of survivin was evaluated, revealing affinities in the low micromolar range.
This easily accessible, new class of survivin-dimerization modulators is an interesting starting point for further lead optimization.
Survivin是一种参与多种细胞通路的关键蛋白。它是凋亡抑制蛋白（IAP）家族的成员，也是染色体乘客复合体的一个组成部分，在该复合体中它通过其二聚化界面与borealin和INCENP结合。通过在其二聚化界面用小分子靶向Survivin，有人提出可以抑制癌细胞的增殖。最近报道了一种小分子二聚化抑制剂Abbott 8。这一系列抑制剂的构效关系表明，中间的吡啶-2(1)-酮环不能耐受任何形式的修饰。
基于使用多组分反应合成Abbott 8的策略，我们合成了一系列带有新型刚性核心支架的小分子。这种刚性化策略是通过将吡啶-2(1)-酮及其6-苯基取代基整合到一个三环结构中实现的，通过不同大小的环将吡啶-2(1)-酮的5位与苯基取代基相连。新的支架是基于Survivin的计算机模拟分子动力学设计的。
评估了这些刚性化支架与Survivin重组L54M突变体的结合情况，结果显示亲和力在低微摩尔范围内。
这种易于获得的新型Survivin二聚化调节剂是进一步进行先导化合物优化的一个有趣起点。
