Morgan Rory K, Kirby Ilsa T, Vermehren-Schmaedick Anke, Rodriguez Kelsie, Cohen Michael S
Program in Chemical Biology, Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon 97210, United States.
ACS Med Chem Lett. 2018 Nov 29;10(1):74-79. doi: 10.1021/acsmedchemlett.8b00429. eCollection 2019 Jan 10.
Poly-ADP-ribose polymerases (PARPs 1-16) have emerged as major regulators of diverse cellular processes. PARPs can be subclassified based on their ability to catalyze poly-ADP-ribosylation (PARylation) or mono-ADP-ribosylation (MARylation). While much is known about the cellular roles of PARPs that catalyze PARylation (e.g., PARP1), the function of PARPs that catalyze MARylation (e.g., PARP10) is substantially less understood. This is due in large part to the lack of small-molecule inhibitors that are selective for individual PARP family members that catalyze MARylation. Herein, we describe the rational design and synthesis of selective inhibitors of PARP10. Using structure-based design, we targeted a hydrophobic subpocket within the nicotinamide-binding site of PARP10. We synthesized a series of small molecules based on a 3,4-dihydroisoquinolin-1(2)-one (dq, ) scaffold that contain various substituents at the C-5 and C-6 positions designed to exploit this hydrophobic subpocket. We found a dq analogue () that contains a methyl group at the C-5 position and a substituted pyridine at the C-6 position that exhibits >10-fold selectivity for PARP10 over a large subset of other PARP family members. The results of this study will serve as a platform for future small-molecule probe development for PARP10 and other PARP family members that catalyze MARylation.
多聚 ADP - 核糖聚合酶（PARPs 1 - 16）已成为多种细胞过程的主要调节因子。PARPs 可根据其催化多聚 ADP - 核糖基化（PARylation）或单 ADP - 核糖基化（MARylation）的能力进行亚分类。虽然对于催化 PARylation 的 PARPs（例如 PARP1）的细胞作用已了解很多，但对于催化 MARylation 的 PARPs（例如 PARP10）的功能了解却少得多。这在很大程度上是由于缺乏对催化 MARylation 的单个 PARP 家族成员具有选择性的小分子抑制剂。在此，我们描述了 PARP10 选择性抑制剂的合理设计与合成。利用基于结构的设计，我们针对 PARP10 烟酰胺结合位点内的一个疏水亚口袋。我们基于 3,4 - 二氢异喹啉 - 1(2) - 酮（dq）支架合成了一系列小分子，这些小分子在 C - 5 和 C - 6 位置含有各种取代基，旨在利用这个疏水亚口袋。我们发现了一种 dq 类似物（），其在 C - 5 位置含有一个甲基，在 C - 6 位置含有一个取代吡啶，与其他大部分 PARP 家族成员相比，对 PARP10 表现出超过 10 倍的选择性。这项研究的结果将为未来开发用于 PARP10 和其他催化 MARylation 的 PARP 家族成员的小分子探针提供一个平台。
