Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Oulu, Finland.
Research Unit of Sustainable Chemistry, Faculty of Technology, University of Oulu, Oulu, Finland.
Bioorg Med Chem. 2021 Dec 15;52:116511. doi: 10.1016/j.bmc.2021.116511. Epub 2021 Nov 10.
The scaffold of TIQ-A, a previously known inhibitor of human poly-ADP-ribosyltransferase PARP1, was utilized to develop inhibitors against human mono-ADP-ribosyltransferases through structure-guided design and activity profiling. By supplementing the TIQ-A scaffold with small structural changes, based on a PARP10 inhibitor OUL35, selectivity changed from poly-ADP-ribosyltransferases towards mono-ADP-ribosyltransferases. Binding modes of analogs were experimentally verified by determining complex crystal structures with mono-ADP-ribosyltransferase PARP15 and with poly-ADP-ribosyltransferase TNKS2. The best analogs of the study achieved 10-20-fold selectivity towards mono-ADP-ribosyltransferases PARP10 and PARP15 while maintaining micromolar potencies. The work demonstrates a route to differentiate compound selectivity between mono- and poly-ribosyltransferases of the human ARTD family.
TIQ-A 是一种已知的人类多聚 ADP-核糖基转移酶 PARP1 抑制剂，我们利用其骨架通过基于结构的设计和活性分析，开发出针对人类单聚 ADP-核糖基转移酶的抑制剂。我们在 TIQ-A 骨架上补充了一些微小的结构变化，这些变化的依据是 PARP10 抑制剂 OUL35，使抑制剂对 PARP10 和 PARP15 的选择性从多聚 ADP-核糖基转移酶变为单聚 ADP-核糖基转移酶。通过与单聚 ADP-核糖基转移酶 PARP15 和多聚 ADP-核糖基转移酶 TNKS2 确定复合物晶体结构，实验验证了类似物的结合模式。研究中最好的类似物对 PARP10 和 PARP15 单聚 ADP-核糖基转移酶的选择性达到 10-20 倍，同时保持微摩尔效力。这项工作展示了一种区分人类 ARTD 家族中单聚和多聚核糖基转移酶化合物选择性的方法。
