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
Editorial
01 March 2024 : Editorial
Editorial: First Regulatory Approvals for CRISPR-Cas9 Therapeutic Gene Editing for Sickle Cell Disease and Transfusion-Dependent β-ThalassemiaDOI: 10.12659/MSM.944204
Med Sci Monit 2024; 30:e944204
In Press
21 Feb 2024 : Clinical Research
Potential Value of HSP90α in Prognosis of Triple-Negative Breast CancerMed Sci Monit In Press; DOI: 10.12659/MSM.943049
22 Feb 2024 : Review article
Differentiation of Native Vertebral Osteomyelitis: A Comprehensive Review of Imaging Techniques and Future ...Med Sci Monit In Press; DOI: 10.12659/MSM.943168
23 Feb 2024 : Clinical Research
A Study of 60 Patients with Low Back Pain to Compare Outcomes Following Magnetotherapy, Ultrasound, Laser, ...Med Sci Monit In Press; DOI: 10.12659/MSM.943732
26 Feb 2024 : Clinical Research
Predictive Value of Combined HbA1c and Neutrophil-to-Lymphocyte Ratio for Diabetic Peripheral Neuropathy in...Med Sci Monit In Press; DOI: 10.12659/MSM.942509
Most Viewed Current Articles
17 Jan 2024 : Review article
Vaccination Guidelines for Pregnant Women: Addressing COVID-19 and the Omicron VariantDOI :10.12659/MSM.942799
Med Sci Monit 2024; 30:e942799
16 May 2023 : Clinical Research
Electrophysiological Testing for an Auditory Processing Disorder and Reading Performance in 54 School Stude...DOI :10.12659/MSM.940387
Med Sci Monit 2023; 29:e940387
14 Dec 2022 : Clinical Research
Prevalence and Variability of Allergen-Specific Immunoglobulin E in Patients with Elevated Tryptase LevelsDOI :10.12659/MSM.937990
Med Sci Monit 2022; 28:e937990
01 Jan 2022 : Editorial
Editorial: Current Status of Oral Antiviral Drug Treatments for SARS-CoV-2 Infection in Non-Hospitalized Pa...DOI :10.12659/MSM.935952
Med Sci Monit 2022; 28:e935952