4L6Z

Human artd3 (parp3) - catalytic domain in complex with inhibitor STO1168

Summary for 4L6Z

• Entry DOI: 10.2210/pdb4l6z/pdb
• Related: 4GV0 4GV2 4GV4 4L70 4L7L 4L7N 4L7O 4L7P 4L7R 4L7U
• Descriptor: Poly [ADP-ribose] polymerase 3, 3-(4-oxo-3,4-dihydroquinazolin-2-yl)-N-[(1S)-1-(pyridin-4-yl)ethyl]propanamide, DIMETHYL SULFOXIDE, ... (4 entities in total)
• Functional Keywords: diphtheria toxin like adp-ribose transferase, transferase, adp-ribosylation, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: Q9Y6F1
• Total number of polymer chains: 1
• Total formula weight: 40152.57

Authors

Karlberg, T.,Thorsell, A.G.,Lindgren, A.E.G.,Ekblad, T.,Spjut, S.,Andersson, C.D.,Weigelt, J.,Linusson, A.,Elofsson, M.,Schuler, H. (deposition date: 2013-06-13, release date: 2014-02-19, Last modification date: 2023-09-20)

Primary citation

Lindgren, A.E.,Karlberg, T.,Ekblad, T.,Spjut, S.,Thorsell, A.G.,Andersson, C.D.,Nhan, T.T.,Hellsten, V.,Weigelt, J.,Linusson, A.,Schuler, H.,Elofsson, M.
Chemical Probes to Study ADP-Ribosylation: Synthesis and Biochemical Evaluation of Inhibitors of the Human ADP-Ribosyltransferase ARTD3/PARP3.
J.Med.Chem., 56:9556-9568, 2013

PubMed Abstract: 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.

PubMed: 24188023
DOI: 10.1021/jm401394u

Experimental method

X-RAY DIFFRACTION (2 Å)