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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 9556-68 (2013)
Related entries: 4l6z, 4l7l, 4l7n, 4l7o, 4l7p, 4l7r, 4l7u

Cited: 4 times
EuropePMC logo PMID: 24188023

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.

Articles citing this publication (4)

  1. PARP3 controls TGFβ and ROS driven epithelial-to-mesenchymal transition and stemness by stimulating a TG2-Snail-E-cadherin axis. Karicheva O, Rodriguez-Vargas JM, Wadier N, Martin-Hernandez K, Vauchelles R, Magroun N, Tissier A, Schreiber V, Dantzer F. Oncotarget 7 64109-64123 (2016)
  2. PARP3, a new therapeutic target to alter Rictor/mTORC2 signaling and tumor progression in BRCA1-associated cancers. Beck C, Rodriguez-Vargas JM, Boehler C, Robert I, Heyer V, Hanini N, Gauthier LR, Tissier A, Schreiber V, Elofsson M, Reina San Martin B, Dantzer F. Cell Death Differ 26 1615-1630 (2019)
  3. The synthesis of (Z)-4-oxo-4-(arylamino)but-2-enoic acids derivatives and determination of their inhibition properties against human carbonic anhydrase I and II isoenzymes. Oktay K, Köse LP, Şendil K, Gültekin MS, Gülçin İ, Supuran CT. J Enzyme Inhib Med Chem 31 939-945 (2016)
  4. The Development of a Biotinylated NAD+-Applied Human Poly(ADP-Ribose) Polymerase 3 (PARP3) Enzymatic Assay. Ji M, Wang L, Xue N, Lai F, Zhang S, Jin J, Chen X. SLAS Discov 23 545-553 (2018)


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