Selective Degradation of Splicing Factor CAPER-alpha by Anticancer Sulfonamides

Target protein degradation is an emerging field in drug discovery and development. In particular, the substrate receptor proteins of the cullin ubiquitin ligase system play a key role in selective protein degradation, which is an essential component of the anti-myeloma activity of immunomodulatory drugs (IMiDs) represented by lenalidomide. Here, we demonstrate that a series of anticancer sulfonamides NSC 719239 (E7820), indisulam, and NSC 339004 (chloroquinoxaline sulfonamide, CQS) induce proteasomal degradation of the U2AF-related splicing factor CAPER-alpha via DCAF15-DDB1-CUL4 CRL4-DCAF15 mediated ubiquitination in human cancer cell lines. Both CRISPR/Cas9-based knockout of DCAF15 and a single amino acid substitution of CAPER-alpha conferred resistance against sulfonamide-induced CAPER-alpha degradation and cell-growth inhibition. Thus, the these sulfonamides represent selective chemical probes for disrupting CAPER-alpha function and designate DCAFs as promising drug targets for promoting selective protein degradation in cancer therapy. Comparison of the siRNA-based genetic perturbation of CAPER/RBM39 (non-target siRNA vs. siRBM39, 20 nM, 48 hours, n = 3) and the E7820-based chemical perturbation of the protein (DMSO vs. E7820, 1 microM, 24 h, n = 3).