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Identification, SAR Studies, and X‐ray Co‐crystallographic Analysis of a Novel Furanopyrimidine Aurora Kinase A Inhibitor
Author(s) -
Coumar Mohane Selvaraj,
Tsai MingTsung,
Chu ChangYing,
Uang BiingJiun,
Lin WenHsing,
Chang ChunYu,
Chang TengYuan,
Leou JiunShyang,
Teng ChiHuang,
Wu JianSung,
Fang MingYu,
Chen ChunHwa,
Hsu John T.A.,
Wu SuYing,
Chao YuSheng,
Hsieh HsingPang
Publication year - 2010
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200900339
Subject(s) - aurora kinase , aurora inhibitor , kinase , chemistry , lead compound , computational biology , stereochemistry , combinatorial chemistry , biochemistry , biology , in vitro , cell cycle , cell
Herein we reveal a simple method for the identification of novel Aurora kinase A inhibitors through substructure searching of an in‐house compound library to select compounds for testing. A hydrazone fragment conferring Aurora kinase activity and heterocyclic rings most frequently reported in kinase inhibitors were used as substructure queries to filter the in‐house compound library collection prior to testing. Five new series of Aurora kinase inhibitors were identified through this strategy, with IC 50 values ranging from ∼300 n M to ∼15 μ M , by testing only 133 compounds from a database of ∼125 000 compounds. Structure–activity relationship studies and X‐ray co‐crystallographic analysis of the most potent compound, a furanopyrimidine derivative with an IC 50 value of 309 n M toward Aurora kinase A, were carried out. The knowledge gained through these studies could help in the future design of potent Aurora kinase inhibitors.