Synthetic mRNA splicing modulator compounds with in vivo antitumor activity.
Lagisetti C, Pourpak A, Goronga T, Jiang Q, Cui X, Hyle J, Lahti JM, Morris SW, Webb TR.
J Med Chem
Cancer Research/Cell Biology
Cells used in publication:
Epithelial, prostate (PrEC), human
Tissue Origin: prostate
Prostate Epithelial Cell Growth Medium
We report our progress on the development of new synthetic anticancer lead compounds that modulate the splicing of mRNA. We also report the synthesis and evaluation of new biologically active ester and carbamate analogues. Further, we describe initial animal studies demonstrating the antitumor efficacy of compound 5 in vivo. Additionally, we report the enantioselective and diastereospecific synthesis of a new 1,3-dioxane series of active analogues. We confirm that compound 5 inhibits the splicing of mRNA in cell-free nuclear extracts and in a cell-based dual-reporter mRNA splicing assay. In summary, we have developed totally synthetic novel spliceosome modulators as therapeutic lead compounds for a number of highly aggressive cancers. Future efforts will be directed toward the more complete optimization of these compounds as potential human therapeutics.
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