title: Selective inhibition of PARP10 using a chemical genetics strategy.
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.
authors.affiliation: 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.
authors.forename: Rory K
authors.initials: RK
authors.lastname: Morgan
authors.affiliation: 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.
authors.forename: Ian
authors.initials: I
authors.lastname: Carter-O'Connell
authors.affiliation: 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.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Cohen
mesh_terms: D020134:Catalytic Domain / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005818:Genetic Engineering; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009154:Mutation; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C000608288:3,4-dihydroisoquinolin-1(2H)-one; D007546:Isoquinolines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011518:Proto-Oncogene Proteins; C499627:PARP10 protein, human; D011065:Poly(ADP-ribose) Polymerases
keywords: ADP-ribosylation; Chemical genetics; Click chemistry; PARPs