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.

Concise Synthesis of (−)-GA18 Methyl Ester

“…Thus, the gibberellins have been used widely and played significant roles in modern agriculture. More recently, gibberellin analogs have been identified as NF-κB pathway inhibitors, demonstrating their potential as anticancer drug leads . Structurally, the gibberellins are tetracyclic diterpene acids that are divided into two classes based on the presence of either 19 or 20 carbons.…”

“…While many C 20 gibberellins are considered as dormant precursors in plants for the bioactive C 19 gibberellins, GA 18 exhibited activities in various plants. For example, in d 1 and d 5 mutants of maize, GA 18 is as active as GA 3 at the dosages of 0.1 and 1 μg per plant . Structurally, GA 18 features the ent -gibberellin tetracyclic core skeleton with eight chiral centers including three all-carbon quaternary centers.…”

“…More recently, gibberellin analogs have been identified as NF-κB pathway inhibitors, demonstrating their potential as anticancer drug leads. 2 Structurally, the gibberellins are tetracyclic diterpene acids that are divided into two classes based on the presence of either 19 or 20 carbons. Gibberellic acid (GA 3 , 2, Figure 1A) is a representative member of the C 19 gibberellins and has lost C-20 and possesses a γ-butyrolactone that links C-4 and C-10.…”

De Novo Diastereoselective Synthesis of 1-Hydroxyl Allogibberic Methyl Ester en Route to Diverse Bioactive Molecules

“…Significantly, it was initially found to display anticancer activity against a series of cell lines. Driven by its unique structure and high potential on the evaluation to bioactive molecules, Schindler and co-workers have devoted continuous efforts to the synthesis and biological evaluation of pharbinilic acid . They primarily developed an efficient semisynthetic approach to pharbinilic acid ( 4 ), in which GA ( 1 ) was converted into 1-hydroxyl allogibberic methyl ester ( 5 ) followed by further installation of the left benzofuran moiety .…”

Presenting a Special Issue on “Medicinal Chemistry: From Targets to Therapies”

“…Thirty-three Letters, two Viewpoints, three Innovations and three Patent Highlights have been contributed by prominent players in their respective fields. Letters cover subjects such as cyclooxygenase 1 detection (by Malerba et al), FAK-targeting PROTACs (Gao et al), a chimeric inhibitor of macrophage migration inhibitory factor (Cirillo et al), Bruton’s tyrosine kinase (BTK) inhibitors (Zhang et al), oximes for acetylcholine esterase reactivation (Gambino et al), Zika virus inhibitors (Coluccia et al), phosphodiesterase 4B (PDE4B) inhibitors (Vadukoot et al), sirtuin 1–3 inhibition (Rajabi et al), analogs of the Gram-negative antibiotic zafirlukast (Howard et al), screens for hepatitis B (HBV) antiviral discovery (Hartman et al), A 3 adenosine receptor (A 3 AR) agonists (Tosh et al), fibroblast growth factor receptor 4 (FGFR4) inhibitors (Liu et al), inactivators of γ-aminobutyric acid aminotransferase (GABA-AT) (Shen et al), bitopic agonists of dopamine D 3 R (Battiti et al), harmaline analogs as COX-2 inhibitors (Uddin et al), imaging approaches in osteoarthritis (Uddin et al), HIV-1 protease inhibitors (Ghosh et al), brain-permeable tafamidis analogs (Sinha et al), melanocortin receptor antagonists (Ericson et al), choline antimetabolites (Bollenbach et al), bromodomain and extra-terminal (BET) inhibitors (Altenburg et al), raltegravir photoaffinity labels (Pala et al), selective orexin-1 antagonists (Préville et al), folate receptor targeting agents (Jin et al), intracellular peptide delivery (Ng et al), gibberellin-based inhibitors of NF-kB (Annand et al), agonists of a cannabinoid-activated GPCR (Schoeder et al), ceramide galactosyltransferase enzyme inhibitors (Thurairatnam et al), thermoresponsive perfluorocarbon hydrogels (Herneisey et al), a sigma-2 receptor agonist that could be effective in COVID-19 (Colabufo et al), a uric acid uptake inhibitor (Uda et al), and cationic photosensitizers (Mazumdar et al) . A Featured Letter describes the discovery of A-1331852, a first-in-class orally active BCL-XL inhibitor that can serve both as a tool compound as well as a lead structure for apoptosis-inducing anticancer drugs (Wang et al) …”