Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15

Abstract

Indisulam is an aryl sulfonamide drug with selective anticancer activity. Its mechanism of action and the basis for its selectivity have so far been unknown. Here we show that indisulam promotes the recruitment of RBM39 (RNA binding motif protein 39) to the CUL4-DCAF15 E3 ubiquitin ligase, leading to RBM39 polyubiquitination and proteasomal degradation. Mutations in RBM39 that prevent its recruitment to CUL4-DCAF15 increase RBM39 stability and confer resistance to indisulam's cytotoxicity. RBM39 associates with precursor messenger RNA (pre-mRNA) splicing factors, and inactivation of RBM39 by indisulam causes aberrant pre-mRNA splicing. Many cancer cell lines derived from hematopoietic and lymphoid lineages are sensitive to indisulam, and their sensitivity correlates with DCAF15 expression levels. Two other clinically tested sulfonamides, tasisulam and chloroquinoxaline sulfonamide, share the same mechanism of action as indisulam. We propose that DCAF15 expression may be a useful biomarker to guide clinical trials of this class of drugs, which we refer to as SPLAMs (splicing inhibitor sulfonamides).

WD40 repeat domain proteins: a novel target class?

“…This molecular glue concept has been elaborated in the form of “protein-targeting chimeric molecules”, or Protacs 111,112 , which in some cases have yielded a phenotypic outcome that is superior to mono-functional ligands inhibiting a specific domain of the target protein 113 . This principle may be more general than anticipated since it was recently found that anticancer sulfonamides ectopically target the oncoprotein RBM39 to the WDR protein DCAF15 for ubiquitination by the CUL4 complex 114,115 . It is not clear yet whether these sulfonamide drugs bind the WDR domain or another region of DCAF15, but E3-associated WDR domains may represent interesting general alternatives to CRBN, with diverse tissue distributions and availability profiles for harnessing chemically the ubiquitin-proteasome system.…”

A Chemoproteomic Approach to Query the Degradable Kinome Using a Multi-kinase Degrader

“…The crystal structure revealed unexpected molecular features including linker folding, linker-protein interactions as well as protein-protein interactions (Gadd et al, 2017). This degrader-induced protein-protein interaction, rather than just proximity between the target protein and an E3 ligase, mirror the actions of the IMiDs (Lu et al, 2014) and the splicing inhibitor sulfonamides (SPLAMs) (Han et al, 2017) at redirecting the substrate profile of an E3 ubiquitin ligase. Considering the protein-protein interactions in ternary complex formation (Gadd et al, 2017) and the reports describing improved target selectivity when an inhibitor is turned into a degrader (Lai et al, 2016; Zengerle et al, 2015), we hypothesized that protein targets are differentially susceptible to degradation mediated by a specific E3 ligase.…”

Proteolysis‐targeting chimeras in drug development: A safety perspective

“…Another class of small molecules that induce targeted protein degradation are the anti‐cancer sulfonamides, which include indisulam, E7820, and CQS (Han et al, ; Uehara et al, ). These compounds function by recruiting neo‐substrates to the E3 ligase DCAF15 for degradation, in a mechanism similar to that used by the IMiDs (Figure ).…”