Here we report [1,2,4]triazolo[3,4-b]benzothiazole (TBT) as a new inhibitor scaffold, which competes with nicotinamide in the binding pocket of human poly- and mono-ADP-ribosylating enzymes. The binding mode was studied through analogs and their crystal structures with TNKS2, PARP2, PARP14 and PARP15. Based on the substitution pattern, we were able to identify The 3-amino derivatives 21 (OUL243) and 27 (OUL232), as inhibitors of mono-ARTs PARP7, PARP10, PARP11, PARP12, PARP14 and PARP15 at nM potencies, with compound 27 being the most potent PARP10 inhibitor described to date with an IC50 of 7.8 nM and the first PARP12 inhibitor ever reported. On the contrary, hydroxy derivative 16 (OUL245) inhibits poly-ARTs with a selectivity towards PARP2. The scaffold does not possess inherent cell toxicity and the inhibitors can enter cells and engage with the target protein. This, together with favorable ADME properties, demonstrates the potential of the TBT scaffold for future drug development efforts towards selective inhibitors against specific enzymes.

中文翻译：

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[1,2,4]三唑并[3,4-b]苯并噻唑支架作为多功能烟酰胺模拟物，可对不同 PARP 酶进行纳摩尔抑制

这里我们报告 [1,2,4]triazolo[3,4- b]苯并噻唑 (TBT) 作为一种新的抑制剂支架，在人多聚和单 ADP 核糖基化酶的结合口袋中与烟酰胺竞争。通过类似物及其与 TNKS2、PARP2、PARP14 和 PARP15 的晶体结构研究结合模式。基于取代模式，我们能够将 3-氨基衍生物 21 (OUL243) 和 27 (OUL232) 鉴定为具有 nM 效力的单一 ARTs PARP7、PARP10、PARP11、PARP12、PARP14 和 PARP15 的抑制剂，与化合物 27是迄今为止描述的最有效的 PARP10 抑制剂，IC50 为 7.8 nM，并且是有史以来第一个报道的 PARP12 抑制剂。相反，羟基衍生物 16 (OUL245) 抑制 poly-ARTs，对 PARP2 具有选择性。支架不具有固有的细胞毒性，抑制剂可以进入细胞并与靶蛋白结合。这个，