Design and synthesis of BPR1K653 derivatives targeting the back pocket of Aurora kinases for selective isoform inhibition

Yi Yu Ke, Chun Ping Chang, Wen Hsing Lin, Chia Hua Tsai, I. Chen Chiu, Wan Ping Wang, Pei Chen Wang, Pei Yi Chen, Wen Hsin Lin, Chun Feng Chang, Po Chu Kuo, Jen Shin Song, Chuan Shih, Hsing Pang Hsieh, Ya Hui Chi

研究成果: Article同行評審

2 引文 斯高帕斯(Scopus)

摘要

Twenty five novel chemical analogs of the previously reported Aurora kinase inhibitor BPR1K653 (1-(4-(2-((5-chloro-6-phenylfuro[2,3-d]pyrimidin-4-yl)amino)ethyl)phenyl)-3-(2-((dimethylamino)methyl)phenyl)urea) have been designed, synthesized, and evaluated by Aurora-A and Aurora-B enzymatic kinase activity assays. Similar to BPR1K653, analogs 3b-3h bear alkyl or tertiary amino group at the ortho position of the phenylurea, and showed equal or better inhibition activity for Aurora-B over Aurora-A. Conversely, preferential Aurora-A inhibition activity was observed when the same functional group was moved to the meta position of the phenylurea. Compounds 3m and 3n, both of which harbor a tertiary amino group at the meta position of the phenylurea, showed 10–16 fold inhibition selectivity for Aurora-A over Aurora-B. The in vitro kinase inhibition results were verified by Western blot analysis, and indicated that compounds 3m and 3n were more than 75-fold superior in inhibiting T-loop autophosphorylation of Aurora-A (Thr288), compared to Aurora-B (Thr232) in HCT116 colon carcinoma cells. The computational docking analysis suggested that the tertiary amine at the meta position of the phenylurea formed a more stable interaction with residues in the back pocket of Aurora-A than in Aurora-B, a possible explanation for the observed discrepancy in the selectivity. These results support an alternative small molecule design strategy targeting the back pocket of Aurora kinases for selective isoform inhibition.

原文English
頁(從 - 到)533-545
頁數13
期刊European Journal of Medicinal Chemistry
151
DOIs
出版狀態Published - 2018 五月 10

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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