1efy

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{{STRUCTURE_1efy| PDB=1efy | SCENE= }}
{{STRUCTURE_1efy| PDB=1efy | SCENE= }}
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'''CRYSTAL STRUCTURE OF THE CATALYTIC FRAGMENT OF POLY (ADP-RIBOSE) POLYMERASE COMPLEXED WITH A BENZIMIDAZOLE INHIBITOR'''
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===CRYSTAL STRUCTURE OF THE CATALYTIC FRAGMENT OF POLY (ADP-RIBOSE) POLYMERASE COMPLEXED WITH A BENZIMIDAZOLE INHIBITOR===
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==Overview==
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The nuclear enzyme poly(ADP-ribose) polymerase (PARP) facilitates the repair of DNA strand breaks and is implicated in the resistance of cancer cells to certain DNA-damaging agents. Inhibitors of PARP have clinical potential as resistance-modifying agents capable of potentiating radiotherapy and the cytotoxicity of some forms of cancer chemotherapy. The preclinical development of 2-aryl-1H-benzimidazole-4-carboxamides as resistance-modifying agents in cancer chemotherapy is described. 1H-Benzimidazole-4-carboxamides, particularly 2-aryl derivatives, are identified as a class of potent PARP inhibitors. Derivatives of 2-phenyl-1H-benzimidazole-4-carboxamide (23, K(i) = 15 nM), in which the phenyl ring contains substituents, have been synthesized. Many of these derivatives exhibit K(i) values for PARP inhibition &lt; 10 nM, with 2-(4-hydroxymethylphenyl)-1H-benzimidazole-4-carboxamide (78, K(i) = 1.6 nM) being one of the most potent. Insight into structure-activity relationships (SAR) for 2-aryl-1H-benzimidazole-4-carboxamides has been enhanced by studying the complex formed between 2-(3-methoxyphenyl)-1H-benzimidazole-4-carboxamide (44, K(i) = 6 nM) and the catalytic domain of chicken PARP. Important hydrogen-bonding and hydrophobic interactions with the protein have been identified for this inhibitor. 2-(4-Hydroxyphenyl)-1H-benzimidazole-4-carboxamide (45, K(i) = 6 nM) potentiates the cytotoxicity of both temozolomide and topotecan against A2780 cells in vitro (by 2.8- and 2.9-fold, respectively).
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{{ABSTRACT_PUBMED_11063605}}
==About this Structure==
==About this Structure==
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[[Category: Inhibitor]]
[[Category: Inhibitor]]
[[Category: Polymerase]]
[[Category: Polymerase]]
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Revision as of 21:38, 30 June 2008

Image:1efy.png

Template:STRUCTURE 1efy

CRYSTAL STRUCTURE OF THE CATALYTIC FRAGMENT OF POLY (ADP-RIBOSE) POLYMERASE COMPLEXED WITH A BENZIMIDAZOLE INHIBITOR

Template:ABSTRACT PUBMED 11063605

About this Structure

1EFY is a Single protein structure of sequence from Gallus gallus. Full crystallographic information is available from OCA.

Reference

Resistance-modifying agents. 9. Synthesis and biological properties of benzimidazole inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase., White AW, Almassy R, Calvert AH, Curtin NJ, Griffin RJ, Hostomsky Z, Maegley K, Newell DR, Srinivasan S, Golding BT, J Med Chem. 2000 Nov 2;43(22):4084-97. PMID:11063605

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