02 May 2003
Pre-clinical development of PARP-1 inhibitors for cancer therapy
N. Curtin, M. Batey, T. Boritzki, C. Calabrese, S. Canan-Koch, R. Griffin, Z. Hostomsky, S. Kyle, D. Newell, I. Stratford, L. Wang, S. Webber, K. WilliamsMed Sci Monit 2003; 9(1): 18-0 :: ID: 15065
Abstract
Both inhibitor and molecular genetic studies demonstrate that impeding PARP-1-mediated DNA repair enhances the cytotoxicity of DNA-damaging cancer therapies. However, the therapeutic potential of this approach has not been investigated previously due to the poor potency, solubility and limited specificity of classical inhibitors. Development of these early benzamide PARP inhibitors (Ki 10 KM) led to the discovery of the more potent inhibitors NU1025 and NU1085. Subsequently, structure-based drug design led to the identification of a very potent, water-soluble PARP-1 inhibitor, AG14361. AG14361 (Ki75% for 4 hours. Non-toxic doses of AG14361 markedly enhanced the antitumour activity of temozolomide, irinotecan and ionising radiation on human tumour xenografts, and AG14361-temozolomide combinations caused complete regression of SW620 xenografts.AG14361 has the required pharmacological properties (potency, specificity, stability and in vivo activity) to address the therapeutic potential of PARP-1 inhibition for the treatment of human cancer.
Keywords: PARP-1 inhibitors, chemotherapy and radiotherapy of cancer, in vitro and in vivo efficacy
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