Rational Design of Cell-Active Inhibitors of PARP10
Version 3 2018-12-11, 15:05
Version 2 2018-12-07, 21:16
Version 1 2018-12-04, 22:44
Posted on 2018-12-11 - 15:05
Poly-ADP-ribose polymerases
(PARPs 1–16) have emerged as
major regulators of diverse cellular processes. PARPs can be subclassified
based on their ability to catalyze poly-ADP-ribosylation (PARylation)
or mono-ADP-ribosylation (MARylation). While much is known about the
cellular roles of PARPs that catalyze PARylation (e.g., PARP1), the
function of PARPs that catalyze MARylation (e.g., PARP10) is substantially
less understood. This is due in large part to the lack of small-molecule
inhibitors that are selective for individual PARP family members that
catalyze MARylation. Herein, we describe the rational design and synthesis
of selective inhibitors of PARP10. Using structure-based design, we
targeted a hydrophobic subpocket within the nicotinamide-binding site
of PARP10. We synthesized a series of small molecules based on a 3,4-dihydroisoquinolin-1(2H)-one (dq, 1) scaffold that contain various
substituents at the C-5 and C-6 positions designed to exploit this
hydrophobic subpocket. We found a dq analogue (22) that
contains a methyl group at the C-5 position and a substituted pyridine
at the C-6 position that exhibits >10-fold selectivity for PARP10
over a large subset of other PARP family members. The results of this
study will serve as a platform for future small-molecule probe development
for PARP10 and other PARP family members that catalyze MARylation.
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Morgan, Rory K.; Kirby, Ilsa T.; Vermehren-Schmaedick, Anke; Rodriguez, Kelsie; Cohen, Michael S. (2018). Rational Design of Cell-Active Inhibitors of PARP10. ACS Publications. Collection. https://doi.org/10.1021/acsmedchemlett.8b00429
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AUTHORS (5)
RM
Rory K. Morgan
IK
Ilsa T. Kirby
AV
Anke Vermehren-Schmaedick
KR
Kelsie Rodriguez
MC
Michael S. Cohen