Herboxidiene (Synonyms: GEX1A, Tan 1609)

Herboxidiene, as a potent antitumor agent, can target the SF3B subunit of the spliceosome. Herboxidiene also induces both G1 and G2/M cell cycle arrest in a human normal fibroblast cell line WI-38.^[1].

In vitro, herboxidiene showed cytotoxicity with IC₅₀ of 0.0037 to approximately 0.99 μM against human tumor cell lines, while herboxidiene were not active against both gram-positive and -negative bacteria.^[3] in addition, Herboxidiene has cytotoxicity against A431, A549, and DLD-1 cells with IC₅₀s of 3.7, 21, 51 nM, respectively.^[6] In vitro efficacy test it shown that in a dose-response assay, 0.5 μM Herboxidiene had substantial inhibitory effects on the plant growth and development comparable to those of 1 μM pladienolide B.^[2] In vitro, treatment with herboxidiene at 5 μM had an effect on cell and nuclei shape, suggesting there is a cellular toxicity at high concentrations.^[4] In addition, herboxidiene (a less potent, structurally different splicing modulator) at 20 nM (∼3 × GI50) in HCT116 cells has the possibility of resistant clone generation.^[5] Herboxidiene has a cytostaticity against human umbilical vein endothelial cells with IC₅₀ of 26 nM and has inhibition with VEGF-induced invasion and tube formation of serum-starved HUVECs in a concentration-dependent manner^[7].

In vivo experiment it exhibited that treatment with 1 mg/kg herboxidiene intraperitoneally once shown obvious antitumor activity^[6].

References:
[1]Ghosh AK, et al. Design and synthesis of herboxidiene derivatives that potently inhibit in vitro splicing. Org Biomol Chem. 2021 Feb 18;19(6):1365-1377.
[2]AlShareef S, et al. Herboxidiene triggers splicing repression and abiotic stress responses in plants. BMC Genomics. 2017 Mar 27;18(1):260.
[3]Sakai Y, et al. GEX1 compounds, novel antitumor antibiotics related to herboxidiene, produced by Streptomyces sp. I. Taxonomy, production, isolation, physicochemical properties and biological activities. J Antibiot (Tokyo). 2002 Oct;55(10):855-62.
[4]Granatosky EA, et al. GEX1A, a Polyketide from Streptomyces chromofuscus, Corrects the Cellular Defects Associated with Niemann-Pick Type C1 in Human Fibroblasts. J Nat Prod. 2018 Sep 28;81(9):2018-2025.
[5]Teng T, et al. Splicing modulators act at the branch point adenosine binding pocket defined by the PHF5A-SF3b complex. Nat Commun. 2017 May 25;8:15522.
[6]Miller-Wideman M, et al. Herboxidiene, a new herbicidal substance from Streptomyces chromofuscus A7847. Taxonomy, fermentation, isolation, physico-chemical and biological properties. J Antibiot (Tokyo). 1992 Jun;45(6):914-21.
[7]Jung HJ, et al. Antiangiogenic activity of herboxidiene via downregulation of vascular endothelial growth factor receptor-2 and hypoxia-inducible factor-1α. Arch Pharm Res. 2015 Sep;38(9):1728-35.