Catalytic poly(ADP-ribose) production by PARP1 is allosterically activated through interaction with DNA breaks, and PARP inhibitor compounds have the potential to influence PARP1 allostery in addition to preventing catalytic activity. Using the benzimidazole-4-carboxamide pharmacophore present in the first generation PARP1 inhibitor veliparib, a series of 11 derivatives was designed, synthesized, and evaluated as allosteric PARP1 inhibitors, with the premise that bulky substituents would engage the regulatory helical domain (HD) and thereby promote PARP1 retention on DNA breaks. We found that core scaffold modifications could indeed increase PARP1 affinity for DNA; however, the bulk of the modification alone was insufficient to trigger PARP1 allosteric retention on DNA breaks. Rather, compounds eliciting PARP1 retention on DNA breaks were found to be rigidly held in a position that interferes with a specific region of the HD domain, a region that is not targeted by current clinical PARP inhibitors. Collectively, these compounds highlight a unique way to trigger PARP1 retention on DNA breaks and open a path to unveil the pharmacological benefits of such inhibitors with novel properties.

中文翻译：

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PARP 抑制剂 veliparib 的新修饰增加了 PARP1 与 DNA 断裂的结合

PARP1 催化聚 (ADP-核糖) 的产生是通过与 DNA 断裂的相互作用以变构方式激活的，PARP 抑制剂化合物除了阻止催化活性之外，还有可能影响 PARP1 变构。利用第一代 PARP1 抑制剂 veliparib 中存在的苯并咪唑-4-甲酰胺药效基团，设计、合成了一系列 11 种衍生物，并作为变构 PARP1 抑制剂进行了评估，前提是庞大的取代基会接合调节螺旋结构域 (HD) 和从而促进 PARP1 在 DNA 断裂时的保留。我们发现核心支架修饰确实可以增加 PARP1 对 DNA 的亲和力；然而，单独的大部分修饰不足以触发DNA断裂时PARP1变构保留。相反，我们发现在 DNA 断裂处引起 PARP1 保留的化合物被严格地固定在干扰 HD 结构域特定区域的位置，而该区域不是当前临床 PARP 抑制剂的目标区域。总的来说，这些化合物突出了一种在 DNA 断裂时触发 PARP1 保留的独特方法，并为揭示此类具有新特性的抑制剂的药理益处开辟了道路。