VP and Chief Medicine Creation Officer & Chief Discovery Officer of Oncology Business Group, Eisai Co., Ltd., Tokyo, Japan
Target protein degradation is an emerging field in drug discovery. 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 clinically-evaluated anticancer sulfonamides E7070 (indisulam), E7820, and CQS (chloroquinoxaline sulfonamide) induce proteasomal degradation of an U2AFrelated splicing factor, Coactivator of Activating Protein-1 and Estrogen Receptors CAPERalpha (also known as RBM39) via CRL4-DCAF15-mediated ubiquitination in human cancer cell lines. Both CRISPR/Cas9-based knockout of DCAF15 and a single amino acid substitution of CAPERalpha conferred resistance against sulfonamide-induced CAPERalpha degradation and cell-growth inhibition. Therefore, these sulfonamides represent a selective inducer of DCAF15-CAPERalpha interaction to disrupt CAPERalpha function and designate DCAFs as promising drug targets in anticancer treatment. While E7107 and H3B-8800, both of which are known as Splicing Factor 3b modulators of the pladienolide class, have been evaluated in Phase 1 clinical trials, the present finding is considered to add an important insight into a growing opportunity of mRNA splicing-targeted anticancer drug discovery. Reference: Uehara, T. et al. Nat. Chem. Biol.13, 675-680 (2017).
Keywords: Anticancer sulfonamides, CAPERalpha, DCAF, RBM39, splicing factor.