posted on 2020-06-19, 01:15authored byJames
R. Annand, Andrew R. Henderson, Kyle S. Cole, Aaron J. Maurais, Jorge Becerra, Yejun Liu, Eranthie Weerapana, Angela N. Koehler, Anna K. Mapp, Corinna S. Schindler
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.