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

preprint
submitted on 16.12.2019 and posted on 20.12.2019 by James Annand, Andrew Henderson, Kyle Cole, Aaron Maurais, Jorge Becerra, Yejun Liu, Eranthie Weerapana, Angela Koehler, Anna Mapp, Corinna Schindler
The small molecule gibberellin JRA-003 (1) 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 IKKalpha (IkB kinase alpha) and IKKbeta (IkB kinase beta). Analogs were synthesized and NF-kB-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 (1) identified as the most potent synthetic gibberellin against cancer-derived cell lines, it displayed no cytotoxicity in cells derived from non-cancerous sources (HEK 293T, HS 578BST, HS 888Lu, HS 895Sk, HUVEC). This selectivity suggests a promising approach for the development of new therapeutics.

Funding

David and Lucile Packard Foundation

Alfred P. Sloan Foundation

Camille and Henry Dreyfus Foundation

Koch Institute Cancer Center Support Core Grant (P30-CA14051)

History

Email Address of Submitting Author

corinnas@umich.edu

Institution

University of Michigan

Country

United States

ORCID For Submitting Author

0000-0003-4968-8013

Declaration of Conflict of Interest

No conflict of interest

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