Identification, SAR studies, and X-ray co-crystallographic analysis of a novel furanopyrimidine aurora kinase A inhibitor.
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.
Coumar
Mohane Selvaraj
MS
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan, Republic of China.
Tsai
Ming-Tsung
MT
Chu
Chang-Ying
CY
Uang
Biing-Jiun
BJ
Lin
Wen-Hsing
WH
Chang
Chun-Yu
CY
Chang
Teng-Yuan
TY
Leou
Jiun-Shyang
JS
Teng
Chi-Huang
CH
Wu
Jian-Sung
JS
Fang
Ming-Yu
MY
Chen
Chun-Hwa
CH
Hsu
John T-A
JT
Wu
Su-Ying
SY
Chao
Yu-Sheng
YS
Hsieh
Hsing-Pang
HP
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
D005663:Furans; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases