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

Abstract

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.

• Authors: James 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
• Journal: ACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 11 Issue 10 Pg. 1913-1918 (Oct 08 2020) ISSN: 1948-5875 [Print] United States
• PMID: 33062173 (Publication Type: Journal Article)