Medicinal Chemistry Group, Faculty of Health Sciences and Medicine, Bond University, Gold Coast, Australia.
Mini Rev Med Chem. 2018;18(19):1659-1669. doi: 10.2174/1389557518666180816111749.
Poly(ADP-ribose)polymerase, member 14 (PARP14, alternatively named ARTD8, BAL2, and COAST6) is an intracellular mono(ADP-ribosyl) transferase. PARP14 transfers a negatively charged ADP-ribose unit from a donor NAD+ molecule onto a target protein, post-translationally. PARP14's domain architecture consists of three macrodomains (Macro1, Macro2 and Macro3), a WWE domain and an ARTD (or catalytic domain). The Macro2 and Macro3 domains bind ADPribose (ADPr) with high affinity, whereas the WWE domain stabilizes the protein structure by binding to ADPr derivatives. The catalytic domain is involved in binding the NAD+ and catalyzing the mono- ADP-ribosylation reaction. PARP14 has been identified as a possible anti-cancer and antiinflammatory target. Acting as a transcriptional co-activator for STAT6, PARP14 acts to promote the over activation of the Th2 immune response, thus promoting the metabolic change to an anaerobic state (Warburg effect) and activation of cell survival pathways through JNK2 and the PGI/AMF complex. These changes are consistent with the metabolic sophistication observed in cancer, and the immune imbalance in inflammatory diseases. Current literature on selective and unselective PARP14 inhibitors are reviewed and discussed. Although there is no evidence that selective PARP inhibitors would be advantageous we have proposed some strategies for future design of selective PARP14 inhibitors.
多聚（ADP-核糖）聚合酶 14 型（PARP14，也称为 ARTD8、BAL2 和 COAST6）是一种细胞内单（ADP-核糖基）转移酶。PARP14 将带负电荷的 ADP-核糖单元从供体 NAD+分子转移到靶蛋白上，进行翻译后修饰。PARP14 的结构域由三个宏结构域（Macro1、Macro2 和 Macro3）、一个 WWE 结构域和一个 ARTD（或催化结构域）组成。Macro2 和 Macro3 结构域与 ADP-核糖（ADPr）具有高亲和力结合，而 WWE 结构域通过与 ADPr 衍生物结合来稳定蛋白质结构。催化结构域参与 NAD+的结合和单 ADP-核糖基化反应的催化。PARP14 已被确定为一种潜在的抗癌和抗炎靶点。作为 STAT6 的转录共激活因子，PARP14 促进 Th2 免疫反应的过度激活，从而促进代谢向厌氧状态（Warburg 效应）的改变，并通过 JNK2 和 PGI/AMF 复合物激活细胞存活途径。这些变化与癌症中观察到的代谢复杂性以及炎症性疾病中的免疫失衡一致。本文综述和讨论了选择性和非选择性 PARP14 抑制剂的相关文献。尽管没有证据表明选择性 PARP 抑制剂会有优势，但我们已经提出了一些未来设计选择性 PARP14 抑制剂的策略。
