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Article Dans Une Revue European Journal of Medicinal Chemistry Année : 2019

Lead optimization and biological evaluation of fragment-based cN-II inhibitors

Résumé

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 to 75% inhibition on the purified recombinant protein at 200 µM and among them three derivatives (12, 13 and 18) exhibited Ki in 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.
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Dates et versions

hal-02371194 , version 1 (20-12-2019)

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Rémi Guillon, Rahila Rahimova, Preeti Preeti, David Egron, Sonia Rouanet, et al.. Lead optimization and biological evaluation of fragment-based cN-II inhibitors. European Journal of Medicinal Chemistry, 2019, 168, pp.28-44. ⟨10.1016/J.EJMECH.2019.02.040⟩. ⟨hal-02371194⟩
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