Selective inhibition of PARP10 using a chemical genetics strategy

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:25

Article

Cohen, Michael S.¹ 

[1] Oregon Hlth & Sci Univ, Program Chem Biol, Portland, OR 97239 USA

关键词: PARPs;    Chemical genetics;    ADP-ribosylation;    Click chemistry;   

DOI  :  10.1016/j.bmcl.2015.07.033

来源: Elsevier

【 摘 要 】

The lack of inhibitors that are selective for individual poly-ADP-ribose polymerase (PARP) family members has limited our understanding of their roles in cells. Here, we describe a chemical genetics approach for generating selective inhibitors of an engineered variant of PARP10. We synthesized a series of C-7 substituted 3,4-dihydroisoquinolin-1(2H)-one (dq) analogues designed to selectively inhibit a mutant of PARP10 (LG-PARP10) that contains a unique pocket in its active site. A dq analogue containing a bromo at the C-7 position demonstrated a 10-fold selectivity for LG-PARP10 compared to its WT counterpart. This study provides a platform for the development of selective inhibitors of individual PARP family members that will be useful for decoding their cellular functions. (C) 2015 Elsevier Ltd. All rights reserved.

【 授权许可】

Free