Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15

Abstract

An old cancer drug's degrading new look Typically, cancer drugs that help only a small number of patients in clinical trials are not pursued. This might change in a future world of precision medicine, where biomarkers will match specific drugs to the patients most likely to respond. Han et al. identified the mechanism of action of a cancer drug called indisulam, a sulfonamide tested previously in patients with solid tumors. Indisulam and related sulfonamides killed cells by disrupting precursor mRNA splicing. The drugs targeted a specific RNA splicing factor for degradation by “gluing” it to the CUL4-DCAF15 ubiquitin ligase. Experiments with cancer cell lines suggest that future clinical trials of these drugs should focus on leukemias and lymphomas with high DCAF15 expression levels. Science , this issue p. eaal3755