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オーラルセッション

第4日　5月18日（金）　10:20～10:40　A会場（オービットホール）

4A-O1-P-1020　　PDF

スルホンアミド抗がん剤によるスプライシング因子CAPERαの選択的分解誘導

(¹エーザイ・ ²兵庫医療大学)
^o上原泰介¹・ 箕嶋幸範¹・ 相根康司¹・ 杉直子¹・ 三橋薫¹・ 山本昇¹・ 神山洋¹・ 高橋健太郎¹・ 小竹良彦¹・ 上杉麻依¹・ 横井晃¹・ 井上篤¹・ 吉田卓¹・ 馬渕美雪²・ 田中明人²・ 大和隆志¹

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.