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
文献索引：10.1016/j.ejmech.2018.03.064
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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.