Design, synthesis and evaluation of potent and selective inhibitors of mono-(ADP-ribosyl)transferases PARP10 and PARP14

被引：32

作者：

Holechek, Jacob ^{[1
]}

Lease, Robert ^{[1
]}

Thorsell, Ann-Gerd ^{[2
]}

Karlberg, Tobias ^{[2
]}

McCadden, Caitlin ^{[1
]}

Grant, Ryan ^{[1
]}

Keen, Abby ^{[1
]}

Callahan, Evan ^{[1
]}

Schuler, Herwig ^{[2
]}

Ferraris, Dana ^{[1
]}

机构：

[1] McDaniel Coll, 2 Coll Hill, Westminster, MD 21157 USA

[2] Karolinska Inst, Dept Biosci & Nutr, Halsovagen 7c, S-14157 Huddinge, Sweden

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2018年 / 28卷 / 11期

基金：

瑞典研究理事会;

关键词：

PARP; PARP10; PARP14; ARTD-8; Mono(ADP-ribosyl) transferase; CANCER;

D O I：

10.1016/j.bmcl.2018.04.056

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 similar to 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. (C) 2018 Elsevier Ltd. All rights reserved.

引用

页码：2050 / 2054

页数：5

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