title: Preclinical selection of a novel poly(ADP-ribose) polymerase inhibitor for clinical trial.
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.
authors.affiliation: Newcastle University, Northern Institute for Cancer Research, Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, United Kingdom.
authors.forename: Huw D
authors.initials: HD
authors.lastname: Thomas
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Calabrese
authors.forename: Michael A
authors.initials: MA
authors.lastname: Batey
authors.forename: Stacie
authors.initials: S
authors.lastname: Canan
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Hostomsky
authors.forename: Suzanne
authors.initials: S
authors.lastname: Kyle
authors.forename: Karen A
authors.initials: KA
authors.lastname: Maegley
authors.forename: David R
authors.initials: DR
authors.lastname: Newell
authors.forename: Donald
authors.initials: D
authors.lastname: Skalitzky
authors.forename: Lan-Zhen
authors.initials: LZ
authors.lastname: Wang
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Webber
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Curtin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000528:radiation effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005720:Gamma Rays; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020714:Maximum Tolerated Dose; D051379:Mice; D008819:Mice, Nude; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013329:Structure-Activity Relationship; D000077204:Temozolomide; D059004:Topoisomerase I Inhibitors; D019772:Topotecan / Q000494:pharmacology
chemical_list: C520469:AG14447; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D059004:Topoisomerase I Inhibitors; D001569:Benzodiazepines; D003606:Dacarbazine; D019772:Topotecan; D011065:Poly(ADP-ribose) Polymerases; D000077204:Temozolomide