biostudies-literatureAnnand JRCamille and Henry Dreyfus FoundationAlfred P. Sloan FoundationDavid and Lucile Packard FoundationNIGMS NIH HHSKoch Institute Cancer Center Support Core Grant1913-1918https://www.ebi.ac.uk/biostudies/studies/S-EPMC7549252biostudies-literatureUnknown11(10)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.ACS medicinal chemistry lettersGibberellin JRA-003: A Selective Inhibitor of Nuclear Translocation of IKKα.PMC7549252R01 GM117004P30-CA14051R35 GM134964Liu YWeerapana EAnnand JRKoehler ANMapp AKCole KSMaurais AJHenderson ARSchindler CSBecerra JfalseGibberellin JRA-003: A Selective Inhibitor of Nuclear Translocation of IKKα.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.2020-01-01T00:00:00Z2020 Oct2024-02-15T17:24:26.307Z2022-02-11T11:52:14.092ZS-EPMC75492523306217310.1021/acsmedchemlett.9b00613