國家衛生研究院 NHRI:Item 3990099045/11114

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Please use this identifier to cite or link to this item: http://ir.nhri.org.tw/handle/3990099045/11114

Title:	Design and synthesis of BPR1K653 derivatives targeting the back pocket of Aurora kinases for selective isoform inhibition
Authors:	Ke, YY;Chang, CP;Lin, WH;Tsai, CH;Chiu, IC;Wang, WP;Wang, PC;Chen, PY;Lin, WH;Chang, CF;Kuo, PC;Song, JS;Shih, C;Hsieh, HP;Chi, YH
Contributors:	Institute of Biotechnology and Pharmaceutical Research
Abstract:	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.
Date:	2018-05-10
Relation:	European Journal of Medicinal Chemistry. 2018 May 10;151:533-545.
Link to:	http://dx.doi.org/10.1016/j.ejmech.2018.03.064
JIF/Ranking 2023:	http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0223-5234&DestApp=IC2JCR
Cited Times(WOS):	https://www.webofscience.com/wos/woscc/full-record/WOS:000432640900040
Cited Times(Scopus):	https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85045234882
Appears in Collections:	[Ya-Hui Chi] Periodical Articles [Hsing-Pang Hsieh] Periodical Articles [Chuan Shih(2014-2017)] Periodical Articles [Chun-Ping Chang] Periodical Articles

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