Selective degradation of splicing factor CAPERα 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), such as 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 coactivator of activating protein-1 and estrogen receptors (CAPER alpha) via 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, 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.