Rory K Morgan1, Ian Carter-O'Connell1, Michael S Cohen2. 1. Program in Chemical Biology and Department of Physiology and Pharmacology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, #L334, Biomedical Research Building, Rm 621, Portland, OR 97239-3098, United States. 2. Program in Chemical Biology and Department of Physiology and Pharmacology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, #L334, Biomedical Research Building, Rm 621, Portland, OR 97239-3098, United States. Electronic address: cohenmic@ohsu.edu.
Abstract
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.
The lack of inhibitors that are selective for individual poly-ADP-ribose polymerase (n class="Gene">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.
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