title: Structural basis for the inhibition of poly(ADP-ribose) polymerases 1 and 2 by BMN 673, a potent inhibitor derived from dihydropyridophthalazinone.
abstract: Poly(ADP-ribose) polymerases 1 and 2 (PARP1 and PARP2), which are involved in DNA damage response, are targets of anticancer therapeutics. BMN 673 is a novel PARP1/2 inhibitor with substantially increased PARP-mediated tumor cytotoxicity and is now in later-stage clinical development for BRCA-deficient breast cancers. In co-crystal structures, BMN 673 is anchored to the nicotinamide-binding pocket via an extensive network of hydrogen-bonding and π-stacking interactions, including those mediated by active-site water molecules. The novel di-branched scaffold of BMN 673 extends the binding interactions towards the outer edges of the pocket, which exhibit the least sequence homology among PARP enzymes. The crystallographic structural analyses reported here therefore not only provide critical insights into the molecular basis for the exceptionally high potency of the clinical development candidate BMN 673, but also new opportunities for increasing inhibitor selectivity.
authors.affiliation: Research and Drug Discovery, BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USA.
authors.forename: Mika
authors.initials: M
authors.lastname: Aoyagi-Scharber
authors.affiliation: Emerald BioStructures, 7869 NE Day Road West, Bainbridge Island, WA 98110, USA.
authors.forename: Anna S
authors.initials: AS
authors.lastname: Gardberg
authors.affiliation: Research and Drug Discovery, BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USA.
authors.forename: Bryan K
authors.initials: BK
authors.lastname: Yip
authors.affiliation: Research and Drug Discovery, BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.affiliation: Research and Drug Discovery, BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USA.
authors.forename: Yuqiao
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Research and Drug Discovery, BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Fitzpatrick
mesh_terms: D000595:Amino Acid Sequence; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D010793:Phthalazines / Q000737:chemistry / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry
chemical_list: D010793:Phthalazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C586365:talazoparib; D011065:Poly(ADP-ribose) Polymerases
keywords: BMN 673; PARP inhibitor; inhibitor design; poly(ADP-ribose) polymerase