國家衛生研究院 NHRI:Item 3990099045/8769
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    题名: Optimization of 5,6-fused pyrimidine-based kinase inhibitors by computer-aided drug design for the treatment of AML
    作者: Hsu, YC;Shiao, HY;Ke, YY;Hsu, JTA;Lin, WH;Chen, CH;Hsieh, HP
    贡献者: Institute of Biotechnology and Pharmaceutical Research
    摘要: FMS-like receptor tyrosine kinase-3 (FLT3), a member of the class III tyrosine kinase receptor family, is expressed by immature hematopoietic cells, and highly associates with acute myeloid leukemia (AML). While acquired resistance to selective FLT3 inhibitors, the treatment became inefficient. Many literatures suggested that dual FLT3-Aurora inhibition may overcome selective FLT3 inhibitor resistance, in part due to inhibition of Aurora kinase, and may benefit patients with FLT3-mutated AML. Thus, utilizing dual FLT3-Aurora inhibitors may be the viable therapy for the treatment of AML. Recently, our group reported a novel AURKA inhibitor by using high-throughput parallel synthesis and structure-based drug design (SBDD). Based on this, we wanted to modify the selective AURKA inhibitor to maintain its Aurora A inhibition as well as improve its FLT3 activity to develop dual FLT3-Aurora kinase inhibitors. Through rapid construction of the platform of FLT3 virtual screening, the lead was quickly and efficiently identified. Proceeding investigation of structure-activity relationship could lead to 6-phenyl pyrrolopyrimidine analogue, showing FLT3 inhibition with an IC50 of 101 nM as well as Aurora kinase A inhibition with an IC50 of 33 nM. To further increase the level of inhibition of FLT3, binding energy calculations and docking study of FLT3 model were introduced to select terminal groups of the side chain with high priority. The selected compounds were synthesized and evaluated the bioactivity. The dramatic antiproliferation of the dual FLT3-AURKA inhibitor against MOLM-13 and MV4-11 (FLT3-ITD (+) human AML cell lines) was observed, and its biologic mechanism of inhibition of FLT3 and Aurora kinase A was proved the by significant evidence of biomarker. For this finding, this novel inhibitor holds potential for further development of preclinical investigations as an anti-AML drug candidate.
    日期: 2014-10
    關聯: Cancer Research. 2014 Oct;74(19 Suppl.):Abstract No. 2530.
    Link to: http://dx.doi.org/10.1158/1538-7445.am2014-2530
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0008-5472&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000349906903267
    显示于类别:[謝興邦] 會議論文/會議摘要
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