Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 168, Issue -, Pages 28-44Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2019.02.040
Keywords
5 '-nucleotidase; Enzyme inhibitor; Cancer
Categories
Funding
- Institut National du Cancer (INCa) [2010-200]
- Agence Nationale de la Recherche (ANR Programme Blanc 2011-SIMI7, cN-II Focus)
- Ligue contre le cancer
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The development of cytosolic 5'-nucleotidase II (cN-II) inhibitors is essential to validate cN-II as a potential target for the reversion of resistance to cytotoxic nucleoside analogues. We previously reported a fragment-based approach combined with molecular modelling, herein, the selected hit-fragments were used again in another computational approach based on the Ilib-diverse (a software enabling to build virtual molecule libraries through fragment based de novo design) program to generate a focused library of potential inhibitors. A molecular scaffold related to a previously identified compound was selected and led to a novel series of compounds. Ten out of nineteen derivatives showed 50-75% inhibition on the purified recombinant protein at 200 AM and among them three derivatives (12,13 and 18) exhibited k(1) the sub-millimolar range (0.84, 2.4 and 0.58 mM, respectively). Despite their only modest potency, the cN-II inhibitors showed synergistic effects when used in combination with cytotoxic purine nucleoside analogues on cancer cells. Therefore, these derivatives represent a family of non-nucleos(t)idic cN-II inhibitors with potential usefulness to overcome cancer drug resistance especially in hematological malignancies in which cN-II activity has been described as an important parameter. (C) 2019 Elsevier Masson SAS. All rights reserved.
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