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Discovery of quinazolinone and quinoxaline derivatives as potent and selective poly(ADP‐ribose) polymerase‐1/2 inhibitors
Author(s) -
Iwashita Akinori,
Hattori Kouji,
Yamamoto Hirofumi,
Ishida Junya,
Kido Yoshiyuki,
Kamijo Kazunori,
Murano Kenji,
Miyake Hiroshi,
Kinoshita Takayoshi,
Warizaya Masaichi,
Ohkubo Mitsuru,
Matsuoka Nobuya,
Mutoh Seitaro
Publication year - 2005
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2005.01.036
Subject(s) - quinazolinone , poly adp ribose polymerase , quinoxaline , chemistry , polymerase , biochemistry , stereochemistry , combinatorial chemistry , enzyme , organic chemistry
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.