國家衛生研究院 NHRI:Item 3990099045/7758

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Title:	Evaluation of the antitumor effects of BPR1J-340, a potent and selective FLT3 inhibitor, alone or in combination with an HDAC inhibitor, vorinostat, in AML cancer
Authors:	Lin, WH;Yeh, TK;Jiaang, WT;Yen, KJ;Chen, CH;Huang, CT;Yen, SC;Hsieh, SY;Chou, LH;Chen, CP;Chiu, CH;Kao, LC;Chao, YS;Chen, CT;Hsu, JTA
Contributors:	Institute of Biotechnology and Pharmaceutical Research
Abstract:	Overexpression or/and activating mutation of FLT3 kinase play a major driving role in the pathogenesis of acute myeloid leukemia (AML). Hence, pharmacologic inhibitors of FLT3 are of therapeutic potential for AML treatment. In this study, BPR1J-340 was identified as a novel potent FLT3 inhibitor by biochemical kinase activity (IC50 approximately 25 nM) and cellular proliferation (GC50 approximately 5 nM) assays. BPR1J-340 inhibited the phosphorylation of FLT3 and STAT5 and triggered apoptosis in FLT3-ITD+ AML cells. The pharmacokinetic parameters of BPR1J-340 in rats were determined. BPR1J-340 also demonstrated pronounced tumor growth inhibition and regression in FLT3-ITD+ AML murine xenograft models. The combination treatment of the HDAC inhibitor vorinostat (SAHA) with BPR1J-340 synergistically induced apoptosis via Mcl-1 down-regulation in MOLM-13 AML cells, indicating that the combination of selective FLT3 kinase inhibitors and HDAC inhibitors could exhibit clinical benefit in AML therapy. Our results suggest that BPR1J-340 may be further developed in the preclinical and clinical studies as therapeutics in AML treatments.
Date:	2014-01-08
Relation:	PLoS ONE. 2014 Jan 8;9(1):Article number e83160.
Link to:	http://dx.doi.org/10.1371/journal.pone.0083160
JIF/Ranking 2023:	http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1932-6203&DestApp=IC2JCR
Cited Times(WOS):	https://www.webofscience.com/wos/woscc/full-record/WOS:000329862500033
Cited Times(Scopus):	http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84897435162
Appears in Collections:	[John Tsu-An Hsu] Periodical Articles [Chiung-Tong Chen] Periodical Articles [Yu-Sheng Chao(2002-2013)] Periodical Articles [Weir-Torn Jiaang] Periodical Articles [Teng-Kuang Yeh] Periodical Articles

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