title: Discovery and Characterization of (8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (BMN 673, Talazoparib), a Novel, Highly Potent, and Orally Efficacious Poly(ADP-ribose) Polymerase-1/2 Inhibitor, as an Anticancer Agent.
abstract: We discovered and developed a novel series of tetrahydropyridophthlazinones as poly(ADP-ribose) polymerase (PARP) 1 and 2 inhibitors. Lead optimization led to the identification of (8S,9R)-47 (talazoparib; BMN 673; (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one). The novel stereospecific dual chiral-center-embedded structure of this compound has enabled extensive and unique binding interactions with PARP1/2 proteins. (8S,9R)-47 demonstrates excellent potency, inhibiting PARP1 and PARP2 enzyme activity with Ki = 1.2 and 0.87 nM, respectively. It inhibits PARP-mediated PARylation in a whole-cell assay with an EC50 of 2.51 nM and prevents proliferation of cancer cells carrying mutant BRCA1/2, with EC50 = 0.3 nM (MX-1) and 5 nM (Capan-1), respectively. (8S,9R)-47 is orally available, displaying favorable pharmacokinetic (PK) properties and remarkable antitumor efficacy in the BRCA1 mutant MX-1 breast cancer xenograft model following oral administration as a single-agent or in combination with chemotherapy agents such as temozolomide and cisplatin. (8S,9R)-47 has completed phase 1 clinical trial and is currently being studied in phase 2 and 3 clinical trials for the treatment of locally advanced and/or metastatic breast cancer with germline BRCA1/2 deleterious mutations.
authors.affiliation: BioMarin Pharmaceutical Inc. , 105 Digital Drive, Novato, California 94949, United States.
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.affiliation: BioMarin Pharmaceutical Inc. , 105 Digital Drive, Novato, California 94949, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Chu
authors.affiliation: BioMarin Pharmaceutical Inc. , 105 Digital Drive, Novato, California 94949, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Feng
authors.affiliation: BioMarin Pharmaceutical Inc. , 105 Digital Drive, Novato, California 94949, United States.
authors.forename: Yuqiao
authors.initials: Y
authors.lastname: Shen
authors.affiliation: BioMarin Pharmaceutical Inc. , 105 Digital Drive, Novato, California 94949, United States.
authors.forename: Mika
authors.initials: M
authors.lastname: Aoyagi-Scharber
authors.affiliation: BioMarin Pharmaceutical Inc. , 105 Digital Drive, Novato, California 94949, United States.
authors.forename: Leonard E
authors.initials: LE
authors.lastname: Post
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D019313:BRCA1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics; D024682:BRCA2 Protein / Q000037:antagonists & inhibitors / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D017321:Clinical Trials, Phase I as Topic; D055808:Drug Discovery; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007700:Kinetics; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D010793:Phthalazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects*; D011485:Protein Binding; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D010793:Phthalazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C586365:talazoparib; C499320:PARP1 protein, human; C483041:PARP2 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases