Selective ERK1/2 agonists isolated from Melia azedarach with potent anti-leukemic activity
Wang,Ning1,2,3; Fan,Yanhua1,2; Yuan,Chun-Mao1,2; Song,Jialei1,2; Yao,Yao1,2; Liu,Wuling1,2; Gajendran,Babu1,2; Zacksenhaus,Eldad3,4; Li,Yanmei1,2; Liu,Jielin5; Hao,Xiao Jiang1,2; Ben-David,Yaacov1,2
Corresponding AuthorLiu,Jielin( ; Hao,Xiao Jiang( ; Ben-David,Yaacov(
Source PublicationBMC Cancer
AbstractAbstractBackgroundMAPK/ERK kinases transmit signals from many growth factors/kinase receptors during normal cell growth/differentiation, and their dysregulation is a hallmark of diverse types of cancers. A plethora of drugs were developed to block this kinase pathway for clinical application. With the exception of a recently identified agent, EQW, most of these inhibitors target upstream factors but not ERK1/2; no activator of ERK1/2 is currently available.MethodA library of compounds isolated from medicinal plants of China was screened for anti-cancer activities. Three limonoid compounds, termed A1541–43, originally isolated from the plant Melia azedarach, exhibiting strong anti-leukemic activity. The anti-neoplastic activity and the biological target of these compounds were explored using various methods, including western blotting, flow cytometry, molecular docking and animal model for leukemia.ResultsCompounds A1541–43, exhibiting potent anti-leukemic activity, was shown to induce ERK1/2 phosphorylation. In contrast, the natural product Cedrelone, which shares structural similarities with A1541–43, functions as a potent inhibitor of ERK1/2. We provided evidence that A1541–43 and Cedrelone specifically target ERK1/2, but not the upstream MAPK/ERK pathway. Computational docking analysis predicts that compounds A1541–43 bind a region in ERK1/2 that is distinct from that to which Cedrelone and EQW bind. Interestingly, both A1541–43, which act as ERK1/2 agonists, and Cedrelone, which inhibit these kinases, exerted strong anti-proliferative activity against multiple leukemic cell lines, and induced robust apoptosis as well as erythroid and megakaryocytic differentiation in erythroleukemic cell lines. These compounds also suppressed tumor progression in a mouse model of erythroleukemia.ConclusionsThis study identifies for the first time activators of ERK1/2 with therapeutic potential for the treatment of cancers driven by dysregulation of the MAPK/ERK pathway and possibly for other disorders.
KeywordCancer Leukemia Chinese medicinal plant Melia azedarach Drug screen ERK1/2 agonists Differentiation Apoptosis
WOS IDBMC:10.1186/s12885-019-5914-8
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Document Type期刊论文
Corresponding AuthorLiu,Jielin; Hao,Xiao Jiang; Ben-David,Yaacov
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GB/T 7714
Wang,Ning,Fan,Yanhua,Yuan,Chun-Mao,et al. Selective ERK1/2 agonists isolated from Melia azedarach with potent anti-leukemic activity[J]. BMC Cancer,2019,19(1).
APA Wang,Ning.,Fan,Yanhua.,Yuan,Chun-Mao.,Song,Jialei.,Yao,Yao.,...&Ben-David,Yaacov.(2019).Selective ERK1/2 agonists isolated from Melia azedarach with potent anti-leukemic activity.BMC Cancer,19(1).
MLA Wang,Ning,et al."Selective ERK1/2 agonists isolated from Melia azedarach with potent anti-leukemic activity".BMC Cancer 19.1(2019).
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