2. Academic Validation
  3. Selective degradation of splicing factor CAPERα by anticancer sulfonamides

Selective degradation of splicing factor CAPERα by anticancer sulfonamides

  • Nat Chem Biol. 2017 Jun;13(6):675-680. doi: 10.1038/nchembio.2363.
Taisuke Uehara 1,  Yukinori Minoshima 1,  Koji Sagane 1,  Naoko Hata Sugi 1,  Kaoru Ogawa Mitsuhashi 1,  Noboru Yamamoto 1,  Hiroshi Kamiyama 1,  Kentaro Takahashi 1,  Yoshihiko Kotake 1,  Mai Uesugi 1,  Akira Yokoi 1,  Atsushi Inoue 1,  Taku Yoshida 1,  Miyuki Mabuchi 2,  Akito Tanaka 2,  Takashi Owa 3
Affiliations

Affiliations

  • 1 Eisai Co., Ltd., Tokodai, Tsukuba-shi, Ibaraki, Japan.
  • 2 School of Pharmacy, Hyogo University of Health Sciences, Minatojima, Chuo-ku, Kobe-shi, Hyogo, Japan.
  • 3 Eisai Inc., Woodcliff Lake, New Jersey, USA.
PMID: 28437394 DOI: 10.1038/nchembio.2363
Abstract

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.

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