Article

Preclinical selection of a novel poly(ADP-ribose) polymerase inhibitor for clinical trial

Newcastle University, Northern Institute for Cancer Research, Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, United Kingdom.
Molecular Cancer Therapeutics (Impact Factor: 6.11). 04/2007; 6(3):945-56. DOI: 10.1158/1535-7163.MCT-06-0552
Source: PubMed

ABSTRACT Poly(ADP-ribose) polymerase (PARP)-1 (EC 2.4.2.30) is a nuclear enzyme that promotes the base excision repair of DNA breaks. Inhibition of PARP-1 enhances the efficacy of DNA alkylating agents, topoisomerase I poisons, and ionizing radiation. Our aim was to identify a PARP inhibitor for clinical trial from a panel of 42 potent PARP inhibitors (K(i), 1.4-15.1 nmol/L) based on the quinazolinone, benzimidazole, tricyclic benzimidazole, tricyclic indole, and tricyclic indole-1-one core structures. We evaluated chemosensitization of temozolomide and topotecan using LoVo and SW620 human colorectal cells; in vitro radiosensitization was measured using LoVo cells, and the enhancement of antitumor activity of temozolomide was evaluated in mice bearing SW620 xenografts. Excellent chemopotentiation and radiopotentiation were observed in vitro, with 17 of the compounds causing a greater temozolomide and topotecan sensitization than the benchmark inhibitor AG14361 and 10 compounds were more potent radiosensitizers than AG14361. In tumor-bearing mice, none of the compounds were toxic when given alone, and the antitumor activity of the PARP inhibitor-temozolomide combinations was unrelated to toxicity. Compounds that were more potent chemosensitizers in vivo than AG14361 were also more potent in vitro, validating in vitro assays as a prescreen. These studies have identified a compound, AG14447, as a PARP inhibitor with outstanding in vivo chemosensitization potency at tolerable doses, which is at least 10 times more potent than the initial lead, AG14361. The phosphate salt of AG14447 (AG014699), which has improved aqueous solubility, has been selected for clinical trial.

0 Followers
 · 
110 Views
  • Source
    • "Dozens of potential PARPi have been screened in vitro and in vivo to select candidates for clinical evaluation as a chemosensitizer in CRC (117). A phase II trial is currently evaluating the efficacy of olaparib in metastatic CRC (mCRC) stratified for MSI status (118). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Poly(ADP-ribose) polymerase inhibitors (PARPi) have shown clinical activity in patients with germline BRCA1/2 mutation (gBRCAm)-associated breast and ovarian cancers. Accumulating evidence suggests that PARPi may have a wider application in the treatment of cancers defective in DNA damage repair pathways, such as prostate, lung, endometrial, and pancreatic cancers. Several PARPi are currently in phase I/II clinical investigation, as single-agents and/or combination therapy in these solid tumors. Understanding more about the molecular abnormalities involved in BRCA-like phenotype in solid tumors beyond breast and ovarian cancers, exploring novel therapeutic trial strategies and drug combinations, and defining potential predictive biomarkers are critical to expanding the scope of PARPi therapy. This will improve clinical outcome in advanced solid tumors. Here, we briefly review the preclinical data and clinical development of PARPi, and discuss its future development in solid tumors beyond gBRCAm-associated breast and ovarian cancers.
    Frontiers in Oncology 02/2014; 4:42. DOI:10.3389/fonc.2014.00042
  • Source
    • "The PARP-1 inhibitor AG014699, a pro-drug of AG014447, has been shown to improve the efficacy of the DNA alkylating agent temozolomide in preclinical models of medulloblastoma [15] and neuroblastoma [16]. Furthermore, the radiosensitizing properties of AG14447 have also been demonstrated in vitro [17], suggesting similar potential for AG014699. AG014699 has been shown to be effective in clinical trials and to induce minimal toxicity in patients [18] [19]. "
  • Source
    • "Presently, this group of compounds has emerged as an important pharmacophore in the development of anticancer agents [4] [5] [6]. For example, a benzimidazole derivative AG14447 was identified by cell based screening assay and was selected for preclinical studies for its anticancer activity [6]. Recently, a benzimidazole compound has been found to selectively inhibit PI3Kb activity and to be effective in PTEN-deficient human tumor model [7]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Here, we have discovered CXI-benzo-84 as a potential anticancer agent from a library of benzimidazole derivatives using cell based screening strategy. CXI-benzo-84 inhibited cell cycle progression in metaphase stage of mitosis and accumulated spindle assembly checkpoint proteins Mad2 and BubR1 on kinetochores, which subsequently activated apoptotic cell death in cancer cells. CXI-benzo-84 depolymerized both interphase and mitotic microtubules, perturbed EB1 binding to microtubules and inhibited the assembly and GTPase activity of tubulin in vitro. CXI-benzo-84 bound to tubulin at a single binding site with a dissociation constant of 1.2±0.2μM. Competition experiments and molecular docking suggested that CXI-benzo-84 binds to tubulin at the colchicine-site. Further, computational analysis provided a significant insight on the binding site of CXI-benzo-84 on tubulin. In addition to its potential use in cancer chemotherapy, CXI-benzo-84 may also be useful to screen colchicine-site agents and to understand the colchicine binding site on tubulin.
    Biochemical pharmacology 06/2013; DOI:10.1016/j.bcp.2013.05.024 · 4.65 Impact Factor
Show more

Preview

Download
0 Downloads
Available from