PDBsum entry 6fxh

Hydrolase

PDB id: 6fxh

Contents

Protein chain

481 a.a.

Ligands

SO4 ×5

GOL ×4

Metals

_MG ×2

Waters ×223

References listed in PDB file

Key reference

• Title: Lead optimization and biological evaluation of fragment-Based cn-Ii inhibitors.
• Authors: R.Guillon, R.Rahimova, Preeti, D.Egron, S.Rouanet, C.Dumontet, N.Aghajari, L.P.Jordheim, L.Chaloin, S.Peyrottes.
• Ref.: Eur J Med Chem, 2019, 168, 28-44. [DOI no: 10.1016/j.ejmech.2019.02.040]
• PubMed id: 30798051

Abstract

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 μM and among them three derivatives (12, 13 and 18) exhibited K_i 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 as an important parameter.