Selective degradation of splicing factor CAPERα by anticancer sulfonamides

Nat Chem Biol. 2017 Jun;13(6):675-680. doi: 10.1038/nchembio.2363. Epub 2017 Apr 24.

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.

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Gene Knockdown Techniques
  • Humans
  • Indoles / pharmacology*
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Proteolysis / drug effects
  • RNA Splicing*
  • RNA-Binding Proteins / chemistry
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Sulfonamides / metabolism*
  • Sulfonamides / pharmacology

Substances

  • Antineoplastic Agents
  • HCC1 autoantigen
  • Indoles
  • N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide
  • Nuclear Proteins
  • RNA-Binding Proteins
  • Sulfonamides
  • N-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzene-sulfonamide

Associated data

  • PubChem-Substance/332854899
  • PubChem-Substance/332854906
  • PubChem-Substance/332854907
  • PubChem-Substance/332854908
  • PubChem-Substance/332854909
  • PubChem-Substance/332854910
  • PubChem-Substance/332854911
  • PubChem-Substance/332854912
  • PubChem-Substance/332854913
  • PubChem-Substance/332854900
  • PubChem-Substance/332854901
  • PubChem-Substance/332854902
  • PubChem-Substance/332854903
  • PubChem-Substance/332854904
  • PubChem-Substance/332854905