日本質量分析学会 第66回質量分析総合討論会

Program

Oral Sessions

Day 4, May 18(Fri.) 10:20-10:40 Room A (OrBit Hall)

Selective Degradation of Splicing Factor CAPERα by Anticancer Sulfonamides

(1Eisai, 2Hyogo University of Health Science)
oTaisuke Uehara1, Yukinori Minoshima1, Koji Sagane1, Naoko Hata1, Kaoru Mitsuhashi1, Noboru Yamamoto1, Hiroshi Kamiyama1, Kentaro Takahashi1, Yoshihiko Kotake1, Mai Uesugi1, Akira Yokoi1, Atsushi Inoue1, Taku Yoshida1, Miyuki Mabuchi2, Akito Tanaka2, Takashi Owa1

Target protein degradation is an emerging field in drug discovery and development. In particular, the DCAF-DDB1-CUL4 ubiquitin ligase system plays 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 the anticancer small molecule sulfonamides E7820, indisulam, and chloroquinoxaline sulfonamide (CQS) induce proteasomal degradation of the U2AF-related splicing factor CAPERα via DCAF15-DDB1-CUL4 mediated ubiquitination. 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, the sulfonamides represent selective chemical probes for disrupting CAPERα function and designate DCAFs as promising drug targets for promoting selective protein degradation in cancer therapy.