Abstract 1125: Spliceosome-targeted antitumor drug discovery

Over the last several years there has been a remarkable convergence of research related to oncogenic aberrations of the spliceosome, which has linked the identification of recurrent spliceosome mutations in tumors to medicinal chemistry. We designed synthetic natural product analogs (the sudemycins) that modulate the activity of the spliceosome and show potent and selective antitumor activity. We hypothesized that splicing gene mutations cause alterations in splice isoforms, which provide a selective advantage to tumor cells, and that perturbation of this environment with spliceosome modulators may cause a selective disadvantage for tumors. To test this hypothesis, we generated MSCV-based retroviruses encoding the wildtype or S34F mutant U2AF1 alleles. We infected c-kit+ primary C57BL/6J murine bone marrow cells with these recombinant retroviruses and cultured them in vitro with cytokine-supplemented media. Vehicle-treated cells expressing the mutant allele had reduced growth over 5 days, compared to cells expressing the wildtype allele or empty vector (P