title: Discovery of quinazolinone and quinoxaline derivatives as potent and selective poly(ADP-ribose) polymerase-1/2 inhibitors.
abstract: Two classes of quinazolinone derivatives and quinoxaline derivatives were identified as potent and selective poly(ADP-ribose) polymerase-1 and 2 (PARP-1) and (PARP-2) inhibitors, respectively. In PARP enzyme assays using recombinant PARP-1 and PARP-2, quinazolinone derivatives displayed relatively high selectivity for PARP-1 and quinoxaline derivatives showed superior selectivity for PARP-2. SBDD analysis via a combination of X-ray structural study and homology modeling suggested distinct interactions of inhibitors with PARP-1 and PARP-2. These findings provide a new structural framework for the design of selective inhibitors for PARP-1 and PARP-2.
authors.affiliation: Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6 Kashima, Osaka 532-8514, Japan. aki_iwashita@po.fujisawa.co.jp
authors.forename: Akinori
authors.initials: A
authors.lastname: Iwashita
authors.forename: Kouji
authors.initials: K
authors.lastname: Hattori
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Junya
authors.initials: J
authors.lastname: Ishida
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kido
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kamijo
authors.forename: Kenji
authors.initials: K
authors.lastname: Murano
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyake
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Kinoshita
authors.forename: Masaichi
authors.initials: M
authors.lastname: Warizaya
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Ohkubo
authors.forename: Nobuya
authors.initials: N
authors.lastname: Matsuoka
authors.forename: Seitaro
authors.initials: S
authors.lastname: Mutoh
mesh_terms: D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D011799:Quinazolines / Q000737:chemistry* / Q000494:pharmacology*; D011810:Quinoxalines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011799:Quinazolines; D011810:Quinoxalines; D011065:Poly(ADP-ribose) Polymerases