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

  • ACS Med Chem Lett. 2020 May 21;11(10):1913-1918. doi: 10.1021/acsmedchemlett.9b00613.
James R Annand  1  2 ,  Andrew R Henderson  2 ,  Kyle S Cole  3 ,  Aaron J Maurais  3 ,  Jorge Becerra  2 ,  Yejun Liu  2 ,  Eranthie Weerapana  3 ,  Angela N Koehler  4 ,  Anna K Mapp  1  2 ,  Corinna S Schindler  1  2
Affiliations
  • 1. Department of Chemistry, Willard-Henry-Dow Laboratory, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United States.
  • 2. Program in Chemical Biology, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, Michigan 48109, United States.
  • 3. Department of Chemistry, Merkert Center, Boston College, 2609 Beacon Street., Chestnut Hill, Massachusetts 02467, United States.
  • 4. David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, Massachusetts 02139, United States.
PMID: 33062173 DOI: 10.1021/acsmedchemlett.9b00613
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.