Program in Chemical Biology, Oregon Health & Science University, Portland, OR 97210, USA; Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, OR 97210, United States.
European Molecular Biology Laboratory (EMBL), Cell Biology and Biophysics Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany; EMBL, Heidelberg University, Heidelberg, Germany.
Cell Chem Biol. 2018 Dec 20;25(12):1547-1553.e12. doi: 10.1016/j.chembiol.2018.09.011. Epub 2018 Oct 18.
Poly-ADP-ribose polymerases (PARPs1-16) play pivotal roles in diverse cellular processes. PARPs that catalyze poly-ADP-ribosylation (PARylation) are the best characterized PARP family members because of the availability of potent and selective inhibitors for these PARPs. There has been comparatively little success in developing selective small-molecule inhibitors of PARPs that catalyze mono-ADP-ribosylation (MARylation), limiting our understanding of the cellular role of MARylation. Here we describe the structure-guided design of inhibitors of PARPs that catalyze MARylation. The most selective analog, ITK7, potently inhibits the MARylation activity of PARP11, a nuclear envelope-localized PARP. ITK7 is greater than 200-fold selective over other PARP family members. Using live-cell imaging, we show that ITK7 causes PARP11 to dissociate from the nuclear envelope. These results suggest that the cellular localization of PARP11 is regulated by its catalytic activity.
多聚 ADP 核糖聚合酶（PARPs1-16）在多种细胞过程中发挥关键作用。由于存在针对这些 PARPs 的有效且选择性抑制剂，因此催化多聚 ADP 核糖基化（PARylation）的 PARPs 是最具特征的 PARP 家族成员。然而，开发选择性的小分子抑制剂来抑制催化单 ADP 核糖基化（MARylation）的 PARPs 方面相对较少，这限制了我们对 MARylation 细胞功能的理解。在这里，我们描述了催化 MARylation 的 PARPs 抑制剂的结构导向设计。最具选择性的类似物 ITK7 可强烈抑制定位于核膜的 PARP11 的 MARylation 活性。ITK7 对其他 PARP 家族成员的选择性大于 200 倍。通过活细胞成像，我们表明 ITK7 导致 PARP11 从核膜解离。这些结果表明 PARP11 的细胞定位受其催化活性调节。
