3 years ago

Selective degradation of splicing factor CAPERα by anticancer sulfonamides

Selective degradation of splicing factor CAPERα by anticancer sulfonamides
Noboru Yamamoto, Koji Sagane, Atsushi Inoue, Akito Tanaka, Taisuke Uehara, Akira Yokoi, Takashi Owa, Yoshihiko Kotake, Kaoru Ogawa Mitsuhashi, Taku Yoshida, Yukinori Minoshima, Mai Uesugi, Hiroshi Kamiyama, Naoko Hata Sugi, Kentaro Takahashi, Miyuki Mabuchi
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 (CAPERα) via CRL4DCAF15 mediated ubiquitination in human cancer cell lines. Both CRISPR–Cas9-based knockout of DCAF15 and a single amino acid substitution of CAPERα conferred resistance against sulfonamide-induced CAPERα degradation and cell-growth inhibition. Thus, these sulfonamides represent selective chemical probes for disrupting CAPERα function and designate DCAFs as promising drug targets for promoting selective protein degradation in cancer therapy.

Publisher URL: http://dx.doi.org/10.1038/nchembio.2363

DOI: 10.1038/nchembio.2363

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