Chemical probes to study ADP-ribosylation: synthesis and biochemical evaluation of inhibitors of the human ADP-ribosyltransferase ARTD3/PARP3.

Lindgren AE, Karlberg T, Ekblad T, Spjut S, Thorsell AG, Andersson CD, Nhan TT, Hellsten V, Weigelt J, Linusson A, Schüler H, Elofsson M

J. Med. Chem. 56 (23) 9556-9568 [2013-12-12; online 2013-11-06]

The racemic 3-(4-oxo-3,4-dihydroquinazolin-2-yl)-N-[1-(pyridin-2-yl)ethyl]propanamide, 1, has previously been identified as a potent but unselective inhibitor of diphtheria toxin-like ADP-ribosyltransferase 3 (ARTD3). Herein we describe synthesis and evaluation of 55 compounds in this class. It was found that the stereochemistry is of great importance for both selectivity and potency and that substituents on the phenyl ring resulted in poor solubility. Certain variations at the meso position were tolerated and caused a large shift in the binding pose. Changes to the ethylene linker that connects the quinazolinone to the amide were also investigated but proved detrimental to binding. By combination of synthetic organic chemistry and structure-based design, two selective inhibitors of ARTD3 were discovered.

Protein Science Facility (PSF)

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PubMed 24188023

DOI 10.1021/jm401394u

Crossref 10.1021/jm401394u

PDB 4L6Z

PDB 4L70

PDB 4L7L

PDB 4L7N

PDB 4L7O

PDB 4L7P

PDB 4L7R

PDB 4L7U