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
| Autor: | Wen Chieh Wang, Yun I. Chang, Fu Ming Kuo, Po Chu Kuo, Ching Ping Chen, Chiung-Tong Chen, Jen Shin Song, Mohane Selvaraj Coumar, Ching Chuan Kuo, Chun Wei Chang, An Siou Li, Ming Hsine Wu, Yi Yu Ke, Teng Kuang Yeh, Sing Yi Wang, Hui Yi Shiao, Kuei Jung Yen, Yung Chang Hsu, Chun Hwa Chen, Wen-Hsing Lin, Hsing Pang Hsieh, John T.A. Hsu, Pei Yi Chen, Chen Lung Huang, Chuan Shih |
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| Rok vydání: | 2016 |
| Předmět: |
Male
Models Molecular 0301 basic medicine Antineoplastic Agents acute myeloid leukemia Rats Sprague-Dawley Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound aurora kinase 0302 clinical medicine Aurora kinase In vivo hemic and lymphatic diseases Cell Line Tumor Neoplasms Drug Discovery Quinazoline Animals Humans Pharmaceutical sciences FLT3 Protein Kinase Inhibitors Aurora Kinase A Kinase Rational design Myeloid leukemia In vitro Rats Leukemia Myeloid Acute 030104 developmental biology fms-Like Tyrosine Kinase 3 Oncology chemistry Drug Design 030220 oncology & carcinogenesis Quinazolines Cancer research multi-kinase inhibitor Research Paper quinazoline |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Yung Chang Hsu 1, * , Mohane Selvaraj Coumar 2, * , Wen-Chieh Wang 1, * , Hui-Yi Shiao 1, * , Yi-Yu Ke 1 , Wen-Hsing Lin 1 , Ching-Chuan Kuo 1 , Chun-Wei Chang 1 , Fu-Ming Kuo 1 , Pei-Yi Chen 1 , Sing-Yi Wang 1 , An-Siou Li 1 , Chun-Hwa Chen 1 , Po-Chu Kuo 1 , Ching-Ping Chen 1 , Ming-Hsine Wu 1 , Chen-Lung Huang 1 , Kuei-Jung Yen 1 , Yun-I Chang 1 , John T.-A. Hsu 1 , Chiung-Tong Chen 1 , Teng-Kuang Yeh 1 , Jen-Shin Song 1 , Chuan Shih 1 , Hsing-Pang Hsieh 1,3 1 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan, ROC 2 Centre for Bioinformatics, School of Life Sciences, Pondicherry University, Kalapet, Puducherry, India 3 Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan, ROC * These authors contributed equally to this work Correspondence to: Hsing-Pang Hsieh, email: hphsieh@nhri.org.tw Keywords: acute myeloid leukemia, aurora kinase, FLT3, quinazoline, multi-kinase inhibitor Received: July 25, 2016 Accepted: November 07, 2016 Published: November 15, 2016 ABSTRACT 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 (IC 50 = 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; IC 50 = 19/22 nM) agents. BPR1K871 showed potent anti-proliferative activities in MOLM-13 and MV4-11 AML cells (EC 50 ~ 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. |
| Databáze: | OpenAIRE |
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