Research Papers:

Discovery of BPR1K871, a quinazoline based, multi-kinase inhibitor for the treatment of AML and solid tumors: Rational design, synthesis, in vitro and in vivo evaluation

Yung Chang Hsu, Mohane Selvaraj Coumar, Wen-Chieh Wang, Hui-Yi Shiao, Yi-Yu Ke, Wen-Hsing Lin, Ching-Chuan Kuo, Chun-Wei Chang, Fu-Ming Kuo, Pei-Yi Chen, Sing-Yi Wang, An-Siou Li, Chun-Hwa Chen, Po-Chu Kuo, Ching-Ping Chen, Ming-Hsine Wu, Chen-Lung Huang, Kuei-Jung Yen, Yun-I Chang, John T.-A. Hsu, Chiung-Tong Chen, Teng-Kuang Yeh, Jen-Shin Song, Chuan Shih and Hsing-Pang Hsieh _

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Oncotarget. 2016; 7:86239-86256. https://doi.org/10.18632/oncotarget.13369

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Yung Chang Hsu1,*, Mohane Selvaraj Coumar2,*, Wen-Chieh Wang1,*, Hui-Yi Shiao1,*, Yi-Yu Ke1, Wen-Hsing Lin1, Ching-Chuan Kuo1, Chun-Wei Chang1, Fu-Ming Kuo1, Pei-Yi Chen1, Sing-Yi Wang1, An-Siou Li1, Chun-Hwa Chen1, Po-Chu Kuo1, Ching-Ping Chen1, Ming-Hsine Wu1, Chen-Lung Huang1, Kuei-Jung Yen1, Yun-I Chang1, John T.-A. Hsu1, Chiung-Tong Chen1, Teng-Kuang Yeh1, Jen-Shin Song1, Chuan Shih1, Hsing-Pang Hsieh1,3

1Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan, ROC

2Centre for Bioinformatics, School of Life Sciences, Pondicherry University, Kalapet, Puducherry, India

3Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan, ROC

*These authors contributed equally to this work

Correspondence to:

Hsing-Pang Hsieh, email: [email protected]

Keywords: acute myeloid leukemia, aurora kinase, FLT3, quinazoline, multi-kinase inhibitor

Received: July 25, 2016     Accepted: November 07, 2016     Published: November 15, 2016


The design and synthesis of a quinazoline-based, multi-kinase inhibitor for the treatment of acute myeloid leukemia (AML) and other malignancies is reported. Based on the previously reported furanopyrimidine 3, quinazoline core containing lead 4 was synthesized and found to impart dual FLT3/AURKA inhibition (IC50 = 127/5 nM), as well as improved physicochemical properties. A detailed structure-activity relationship study of the lead 4 allowed FLT3 and AURKA inhibition to be finely tuned, resulting in AURKA selective (5 and 7; 100-fold selective over FLT3), FLT3 selective (13; 30-fold selective over AURKA) and dual FLT3/AURKA selective (BPR1K871; IC50 = 19/22 nM) agents. BPR1K871 showed potent anti-proliferative activities in MOLM-13 and MV4-11 AML cells (EC50 ~ 5 nM). Moreover, kinase profiling and cell-line profiling revealed BPR1K871 to be a potential multi-kinase inhibitor. Functional studies using western blot and DNA content analysis in MV4-11 and HCT-116 cell lines revealed FLT3 and AURKA/B target modulation inside the cells. In vivo efficacy in AML xenograft models (MOLM-13 and MV4-11), as well as in solid tumor models (COLO205 and Mia-PaCa2), led to the selection of BPR1K871 as a preclinical development candidate for anti-cancer therapy. Further detailed studies could help to investigate the full potential of BPR1K871 as a multi-kinase inhibitor.

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