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Gibberellin JRA-003: A Selective Inhibitor of Nuclear Translocation of IKKalpha
preprintsubmitted on 16.12.2019, 23:11 and posted on 20.12.2019, 09:54 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.