title: Identification, SAR studies, and X-ray co-crystallographic analysis of a novel furanopyrimidine aurora kinase A inhibitor.
abstract: 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 approximately 300 nM to approximately 15 microM, by testing only 133 compounds from a database of approximately 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 nM toward Aurora kinase A, were carried out. The knowledge gained through these studies could help in the future design of potent Aurora kinase inhibitors.
authors.affiliation: Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan, Republic of China.
authors.forename: Mohane Selvaraj
authors.initials: MS
authors.lastname: Coumar
authors.forename: Ming-Tsung
authors.initials: MT
authors.lastname: Tsai
authors.forename: Chang-Ying
authors.initials: CY
authors.lastname: Chu
authors.forename: Biing-Jiun
authors.initials: BJ
authors.lastname: Uang
authors.forename: Wen-Hsing
authors.initials: WH
authors.lastname: Lin
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Chang
authors.forename: Teng-Yuan
authors.initials: TY
authors.lastname: Chang
authors.forename: Jiun-Shyang
authors.initials: JS
authors.lastname: Leou
authors.forename: Chi-Huang
authors.initials: CH
authors.lastname: Teng
authors.forename: Jian-Sung
authors.initials: JS
authors.lastname: Wu
authors.forename: Ming-Yu
authors.initials: MY
authors.lastname: Fang
authors.forename: Chun-Hwa
authors.initials: CH
authors.lastname: Chen
authors.forename: John T-A
authors.initials: JT
authors.lastname: Hsu
authors.forename: Su-Ying
authors.initials: SY
authors.lastname: Wu
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Chao
authors.forename: Hsing-Pang
authors.initials: HP
authors.lastname: Hsieh
mesh_terms: D064127:Aurora Kinases; D001665:Binding Sites; D018360:Crystallography, X-Ray; D005663:Furans / Q000737:chemistry*; D057166:High-Throughput Screening Assays; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D005663:Furans; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases