6FIW
Human cytosolic 5'-nucleotidase II co-crystallized with 10mM Sodium ((4-(3'-((7H-purin-6-yl)carbamoyl)-[1,1'-biphenyl]-3-yl)-1H-imidazol-1-yl) methyl) phosphonate
Summary for 6FIW
| Entry DOI | 10.2210/pdb6fiw/pdb |
| Related | 2J2C 4H4B 5CQZ 5CR7 6FIR 6FIS 6FIU |
| Descriptor | Cytosolic purine 5'-nucleotidase, SULFATE ION, MAGNESIUM ION, ... (5 entities in total) |
| Functional Keywords | hydrolase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 62548.41 |
| Authors | Aghajari, N.,Preeti, P. (deposition date: 2018-01-19, release date: 2019-01-30, Last modification date: 2024-05-08) |
| Primary citation | Guillon, R.,Rahimova, R.,Egron, D.,Rouanet, S.,Dumontet, C.,Aghajari, N.,Jordheim, L.P.,Chaloin, L.,Peyrottes, S. Lead optimization and biological evaluation of fragment-based cN-II inhibitors. Eur J Med Chem, 168:28-44, 2019 Cited by PubMed 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 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. PubMed: 30798051DOI: 10.1016/j.ejmech.2019.02.040 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.2 Å) |
Structure validation
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