Structural Genomics Consortium, University of Oxford, ORCRB, Old Road Campus, Headington, Oxford, Oxfordshire OX3 7DQ, UK; Target Discovery Institute, University of Oxford, NDM Research Building, Old Road Campus, Headington, Oxford, Oxfordshire OX3 7FZ, UK; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, UK.
Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians University, Munich 81377, Germany.
Bioorg Med Chem. 2018 Jul 15;26(11):2965-2972. doi: 10.1016/j.bmc.2018.03.020. Epub 2018 Mar 12.
The polyadenosine-diphosphate-ribose polymerase 14 (PARP14) has been implicated in DNA damage response pathways for homologous recombination. PARP14 contains three (ADP ribose binding) macrodomains (MD) whose exact contribution to overall PARP14 function in pathology remains unclear. A medium throughput screen led to the identification of N-(2(-9H-carbazol-1-yl)phenyl)acetamide (GeA-69, 1) as a novel allosteric PARP14 MD2 (second MD of PARP14) inhibitor. We herein report medicinal chemistry around this novel chemotype to afford a sub-micromolar PARP14 MD2 inhibitor. This chemical series provides a novel starting point for further development of PARP14 chemical probes.
多聚腺苷二磷酸核糖聚合酶 14（PARP14）已被牵涉到同源重组的 DNA 损伤反应途径中。PARP14 包含三个（ADP 核糖结合）宏结构域（MD），但其在病理学中的整体 PARP14 功能的具体贡献仍不清楚。一项中等通量筛选导致了 N-(2-(9H-咔唑-1-基)苯基)乙酰胺（GeA-69，1）的鉴定，它是一种新型的别构 PARP14 MD2（PARP14 的第二个 MD）抑制剂。我们在此报告了围绕这种新型化学型的药物化学研究，以提供一种亚微摩尔 PARP14 MD2 抑制剂。这个化学系列为进一步开发 PARP14 化学探针提供了一个新的起点。
