title: Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib.
abstract: Anti-PARP drugs were initially developed as catalytic inhibitors to block the repair of DNA single-strand breaks. We recently reported that several PARP inhibitors have an additional cytotoxic mechanism by trapping PARP-DNA complexes, and that both olaparib and niraparib act as PARP poisons at pharmacologic concentrations. Therefore, we have proposed that PARP inhibitors should be evaluated based both on catalytic PARP inhibition and PARP-DNA trapping. Here, we evaluated the novel PARP inhibitor, BMN 673, and compared its effects on PARP1 and PARP2 with two other clinical PARP inhibitors, olaparib and rucaparib, using biochemical and cellular assays in genetically modified chicken DT40 and human cancer cell lines. Although BMN 673, olaparib, and rucaparib are comparable at inhibiting PARP catalytic activity, BMN 673 is ∼100-fold more potent at trapping PARP-DNA complexes and more cytotoxic as single agent than olaparib, whereas olaparib and rucaparib show similar potencies in trapping PARP-DNA complexes. The high level of resistance of PARP1/2 knockout cells to BMN 673 demonstrates the selectivity of BMN 673 for PARP1/2. Moreover, we show that BMN 673 acts by stereospecific binding to PARP1 as its enantiomer, LT674, is several orders of magnitude less efficient. BMN 673 is also approximately 100-fold more cytotoxic than olaparib and rucaparib in combination with the DNA alkylating agents methyl methane sulfonate (MMS) and temozolomide. Our study demonstrates that BMN 673 is the most potent clinical PARP inhibitor tested to date with the highest efficiency at trapping PARP-DNA complexes.
authors.affiliation: Corresponding Author: Yves Pommier, Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, 37 Convent Drive, Building 37, Room 5068, NIH, Bethesda, MD 20892-4255. pommier@nih.gov.
authors.forename: Junko
authors.initials: J
authors.lastname: Murai
authors.forename: Shar-Yin N
authors.initials: SY
authors.lastname: Huang
authors.forename: Amèlie
authors.initials: A
authors.lastname: Renaud
authors.forename: Yiping
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jiuping
authors.initials: J
authors.lastname: Ji
authors.forename: Shunichi
authors.initials: S
authors.lastname: Takeda
authors.forename: Joel
authors.initials: J
authors.lastname: Morris
authors.forename: Beverly
authors.initials: B
authors.lastname: Teicher
authors.forename: James H
authors.initials: JH
authors.lastname: Doroshow
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005454:Fluorescence Polarization; D006801:Humans; D015151:Immunoblotting; D007211:Indoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D015394:Molecular Structure; D010793:Phthalazines / Q000737:chemistry / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism; D000077204:Temozolomide
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D003606:Dacarbazine; C531549:rucaparib; D000255:Adenosine Triphosphate; D004247:DNA; C586365:talazoparib; D008741:Methyl Methanesulfonate; D011065:Poly(ADP-ribose) Polymerases; C531550:olaparib; D000077204:Temozolomide