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: 5.68). 04/2007; 6(3):945-56. DOI: 10.1158/1535-7163.MCT-06-0552
Source: PubMed


Poly(ADP-ribose) polymerase (PARP)-1 (EC 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.

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Available from: Karen Maegley, Sep 21, 2015
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    • "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). "
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    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
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    • "As single-agent high doses and long exposures are nontoxic, but in combination with cytotoxic agents only lower doses and shorter exposures are tolerated. Singleagent rucaparib was nontoxic to mice on a repeated 5-day schedule at a dose of 50 mg kg À 1 for 6 months, but in combination with temozolomide 1 mg kg À 1 daily for five days was the effective but maximum tolerated dose (Thomas et al, 2007; Drew et al, 2011). Data emerging from the clinic also show that tolerable doses of single-agent PARPi frequently result in grade 3/4 myelosuppression in chemotherapy combination studies requiring dose reduction of the companion cytotoxic agent (Do and Chen, 2013). "
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    ABSTRACT: Background: Poly(ADP-ribose) polymerase-1 (PARP) inhibitors (PARPi) exploit tumour-specific defects in homologous recombination DNA repair and continuous dosing is most efficacious. Early clinical trial data with rucaparib suggested that it caused sustained PARP inhibition. Here we investigate the mechanism of this durable inhibition and potential exploitation. Methods: Uptake and retention of rucaparib and persistence of PARP inhibition were determined by radiochemical and immunological assays in human cancer cell lines. The pharmacokinetics and pharmacodynamics of rucaparib were determined in tumour-bearing mice and the efficacy of different schedules of rucaparib was determined in mice bearing homologous recombination DNA repair-defective tumours. Results: Rucaparib accumulation is carrier mediated (Km=8.4±1.2 μM, Vmax=469±22 pmol per 106 cells per 10 min), reaching steady-state levels >10 times higher than the extracellular concentration within 30 min. Rucaparib is retained in cells and inhibits PARP ⩾50% for ⩾72 h days after a 30-min pulse of 400 nM. In Capan-1 tumour-bearing mice rucaparib accumulated and was retained in the tumours, and PARP was inhibited for 7 days following a single dose of 10 mg kg−1 i.p or 150 mg kg−1 p.o. by 70% and 90%, respectively. Weekly dosing of 150 mg kg−1 p.o once a week was as effective as 10 mg kg−1 i.p daily for five days every week for 6 weeks in delaying Capan-1 tumour growth. Conclusions: Rucaparib accumulates and is retained in tumour cells and inhibits PARP for long periods such that weekly schedules have equivalent anticancer activity to daily dosing in a pre-clinical model, suggesting that clinical evaluation of alternative schedules of rucaparib should be considered.
    British Journal of Cancer 02/2014; 110(8). DOI:10.1038/bjc.2014.91 · 4.84 Impact Factor
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    • "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]. "

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