Gibberellin JRA-003: A Selective Inhibitor of Nuclear Translocation of IKKα

被引：9

作者：

Annand, James R. ^{[1
,2
]}

Henderson, Andrew R. ^{[2
]}

Cole, Kyle S. ^{[3
]}

Maurais, Aaron J. ^{[3
]}

Becerra, Jorge ^{[2
]}

Liu, Yejun ^{[2
]}

Weerapana, Eranthie ^{[3
]}

Koehler, Angela N. ^{[4
]}

Mapp, Anna K. ^{[1
,2
]}

Schindler, Corinna S. ^{[1
,2
]}

机构：

[1] Univ Michigan, Willard Henry Dow Lab, Dept Chem, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Program Chem Biol, Ann Arbor, MI 48109 USA

[3] Boston Coll, Merkert Ctr, Dept Chem, Chestnut Hill, MA 02467 USA

[4] MIT, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2020年 / 11卷 / 10期

关键词：

Nuclear kappa-light-chain-enhancer of activated B cells (NF-kappa B); I kappa B kinase (IKK); gibberellins; inhibition of nuclear translocation; NF-KAPPA-B; KINASE-ALPHA; CANCER; TRANSCRIPTION; INFLAMMATION; EXPRESSION; ACID; IDENTIFICATION; PROGRESSION; METASTASIS;

D O I：

10.1021/acsmedchemlett.9b00613

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The small molecule gibberellin JRA-003 was identified as an inhibitor of the NF-kB (nuclear kappa-lightchain-enhancer of activated B cells) pathway. Here we find that JRA-003 binds to and significantly inhibits the nuclear translocation of pathway-activating kinases IKK alpha (I kappa B kinase alpha) and IKK beta (I kappa B kinase beta). Analogs of JRA-003 were synthesized and NF-kappa B-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.

引用

页码：1913 / 1918

页数：6

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