1EFY

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

Summary for 1EFY

• Entry DOI: 10.2210/pdb1efy/pdb
• Related: 1PAX 2PAW 2PAX 3PAX 4PAX
• Descriptor: POLY (ADP-RIBOSE) POLYMERASE, 2-(3'-METHOXYPHENYL) BENZIMIDAZOLE-4-CARBOXAMIDE (3 entities in total)
• Functional Keywords: benzimidazole, inhibitor, catalytic fragment, polymerase, transferase
• Biological source: Gallus gallus (chicken)
• Cellular location: Nucleus : P26446
• Total number of polymer chains: 1
• Total formula weight: 39595.42

Authors

White, A.W.,Almassy, R.,Calvert, A.H.,Curtin, N.J.,Griffin, R.J.,Hostomsky, Z.,Maegley, K.,Newell, D.R.,Srinivasan, S.,Golding, B.T. (deposition date: 2000-02-10, release date: 2001-01-17, Last modification date: 2024-02-07)

Primary citation

White, A.W.,Almassy, R.,Calvert, A.H.,Curtin, N.J.,Griffin, R.J.,Hostomsky, Z.,Maegley, K.,Newell, D.R.,Srinivasan, S.,Golding, B.T.
Resistance-modifying agents. 9. Synthesis and biological properties of benzimidazole inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase.
J.Med.Chem., 43:4084-4097, 2000

PubMed Abstract: 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 < 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).

PubMed: 11063605
DOI: 10.1021/jm000950v

Experimental method

X-RAY DIFFRACTION (2.2 Å)