Discovery of quinazolinone and quinoxaline derivatives as potent and selective poly(ADP-ribose) polymerase-1/2 inhibitors.
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.
Iwashita
Akinori
A
Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6 Kashima, Osaka 532-8514, Japan. aki_iwashita@po.fujisawa.co.jp
Hattori
Kouji
K
Yamamoto
Hirofumi
H
Ishida
Junya
J
Kido
Yoshiyuki
Y
Kamijo
Kazunori
K
Murano
Kenji
K
Miyake
Hiroshi
H
Kinoshita
Takayoshi
T
Warizaya
Masaichi
M
Ohkubo
Mitsuru
M
Matsuoka
Nobuya
N
Mutoh
Seitaro
S
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
D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011799:Quinazolines; D011810:Quinoxalines; D011065:Poly(ADP-ribose) Polymerases