Holechek Jacob, Lease Robert, Thorsell Ann-Gerd, Karlberg Tobias, McCadden Caitlin, Grant Ryan, Keen Abby, Callahan Evan, Schüler Herwig, Ferraris Dana
McDaniel College, 2 College Hill, Westminster, MD 21157, United States.
Karolinska Institutet, Department of Biosciences and Nutrition, Hälsovägen 7c, S-14157 Huddinge, Sweden.
Bioorg Med Chem Lett. 2018 Jun 15;28(11):2050-2054. doi: 10.1016/j.bmcl.2018.04.056. Epub 2018 May 3.
A series of diaryl ethers were designed and synthesized to discern the structure activity relationships against the two closely related mono-(ADP-ribosyl)transferases PARP10 and PARP14. Structure activity studies identified 8b as a sub-micromolar inhibitor of PARP10 with ∼15-fold selectivity over PARP14. In addition, 8k and 8m were discovered to have sub-micromolar potency against PARP14 and demonstrated moderate selectivity over PARP10. A crystal structure of the complex of PARP14 and 8b shows binding of the compound in a novel hydrophobic pocket and explains both potency and selectivity over other PARP family members. In addition, 8b, 8k and 8m also demonstrate selectivity over PARP1. Together, this study identified novel, potent and metabolically stable derivatives to use as chemical probes for these biologically interesting therapeutic targets.
设计并合成了一系列二芳基醚，以确定其对两种密切相关的单（ADP - 核糖基）转移酶PARP10和PARP14的构效关系。构效关系研究确定8b为PARP10的亚微摩尔抑制剂，对PARP14具有约15倍的选择性。此外，发现8k和8m对PARP14具有亚微摩尔效力，并对PARP10表现出适度的选择性。PARP14与8b复合物的晶体结构显示该化合物结合在一个新的疏水口袋中，并解释了其对其他PARP家族成员的效力和选择性。此外，8b、8k和8m对PARP1也表现出选择性。总之，本研究确定了新型、强效且代谢稳定的衍生物，可作为这些具有生物学意义的治疗靶点的化学探针。
