Gibberellin JRA-003: A Selective Inhibitor of Nuclear Translocation of IKKα,ACS Medicinal Chemistry Letters

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Gibberellin JRA-003: A Selective Inhibitor of Nuclear Translocation of IKKα
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-05-21 , DOI: 10.1021/acsmedchemlett.9b00613
James R Annand _{1,

2} , Andrew R Henderson ₂ , Kyle S Cole ₃ , Aaron J Maurais ₃ , Jorge Becerra ₂ , Yejun Liu ₂ , Eranthie Weerapana ₃ , Angela N Koehler ₄ , Anna K Mapp _{1,

2} , Corinna S Schindler _{1,

2}

Affiliation

The small molecule gibberellin JRA-003 was identified as an inhibitor of the NF-kB (nuclear kappa-light-chain-enhancer of activated B cells) pathway. Here we find that JRA-003 binds to and significantly inhibits the nuclear translocation of pathway-activating kinases IKKα (IκB kinase alpha) and IKKβ (IκB kinase beta). Analogs of JRA-003 were synthesized and NF-κB-inhibiting gibberellins were found to be cytotoxic in cancer-derived cell lines (HS 578T, HCC 1599, RC-K8, Sud-HL4, CA 46, and NCIH 4466). Not only was JRA-003 identified as the most potent synthetic gibberellin against cancer-derived cell lines, it displayed no cytotoxicity in cells derived from noncancerous sources (HEK 293T, HS 578BST, HS 888Lu, HS 895Sk, HUVEC). This selectivity suggests a promising approach for the development of new therapeutics.

中文翻译：

赤霉素 JRA-003：IKKα 核转位的选择性抑制剂

小分子赤霉素 JRA-003 被鉴定为 NF-kB（活化 B 细胞的核 kappa-轻链增强子）途径的抑制剂。在这里我们发现 JRA-003 结合并显着抑制通路激活激酶 IKKα（IκB 激酶 α）和 IKKβ（IκB 激酶β）的核转位。合成了 JRA-003 的类似物，发现抑制 NF-κB 的赤霉素在癌症衍生细胞系（HS 578T、HCC 1599、RC-K8、Sud-HL4、CA 46 和 NCIH 4466）中具有细胞毒性。JRA-003 不仅被鉴定为对抗癌衍生细胞系最有效的合成赤霉素，而且在非癌来源（HEK 293T、HS 578BST、HS 888Lu、HS 895Sk、HUVEC）衍生的细胞中没有显示细胞毒性。这种选择性为开发新疗法提供了一种很有前景的方法。

更新日期：2020-05-21

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