Aryl Sulfonamides Degrade RBM39 and RBM23 by Recruitment to CRL4-DCAF15
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Indisulam and related sulfonamides recruit the splicing factor RBM39 to the CRL4-DCAF15 E3 ubiquitin ligase, resulting in RBM39 ubiquitination and degradation. Here, we used a combination of domain mapping and random mutagenesis to identify domains or residues that are necessary for indisulam-dependent RBM39 ubiquitination. DCAF15 mutations at Q232 or D475 prevent RBM39 recruitment by indisulam. RBM39 is recruited to DCAF15 by its RRM2 (RNA recognition motif 2) and is ubiquitinated on its N terminus. RBM23, which is an RBM39 paralog, is also recruited to the CRL4-DCAF15 ligase through its RRM2 domain and undergoes sulfonamide-dependent degradation. Indisulam alters the expression of more than 3,000 genes and causes widespread intron retention and exon skipping. All of these changes can be attributed to RBM39, and none are the consequence of RBM23 degradation. Our findings demonstrate that indisulam selectively degrades RBM23 and RBM39, the latter of which is critically important for splicing and gene expression.
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The same MG mechanism has been revealed for antitumor aryl-sulfonamides, which reprogram DCAF15 to bind and degrade certain RNA-binding proteins.
“The same MG mechanism has subsequently been revealed for antitumor aryl-sulfonamides, which reprograms another CRL4 substrate receptor, DCAF15, to bind and degrade certain RNA-binding proteins21–26.”
From Defining molecular glues with a dual-nanobody cannabidiol sensor (2022) · cites this paper as [23]
Additional MGDs have been reported that induce degradation of proteins devoid of obvious ligand-binding pockets, such as RBM39 or cyclin K.
“Additional MGDs have been reported, which induce the degradation of proteins devoid of obvious ligand-binding pockets, such as RBM3954−57 or cyclin K (CycK).58−60”
From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [55]
Sulfonamides previously in clinical trials use DCAF15 to degrade RBM39 via a molecular glue mechanism.
“sulfonamides previously in clinical trials81,82 that have since been shown to use DCAF15 to degrade RBM39 (refs25,27,29), also via a molecular glue mechanism”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [29]
CR8, originally developed as a CDK inhibitor, acts as a first-in-class molecular glue degrader of cyclin K.
“Firstly, by mining correlations between drug sensitivity and the gene-expression profiles of E3 ubiquitin ligase components in hundreds of cell lines, it was discovered that CR8, which was originally developed as a cyclin-dependent kinase (CDK) inhibitor, acts as a first-in-class molecular glue degrader of cyclin K182.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [182]
Two additional, entirely distinct classes of small-molecule molecular glue degraders have been discovered.
“Two additional, entirely distinct classes of small-molecule molecular glue degraders have been discovered.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [182]
Structurally divergent small molecules all directly engage a substrate receptor-less CUL4 E3 ligase complex by binding to DDB1 while interacting with and recruiting CDK12 in complex with cyclin K.
“Remarkably, these structurally divergent small molecules all directly engage a substrate receptor-less CUL4 E3 ligase complex by binding to its substrate adaptor component, DDB1, whilst simultaneously interacting with and thereby recruiting CDK12 in complex with cyclin K.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [182]
Selective complementarity between the surfaces of DDB1 and CDK12 holds promise for future development of cyclin K degrader therapeutics.
“Thus, selective complementarity between the surfaces of DDB1 and CDK12 hold promise for the future development of cyclin K degrader therapeutics182.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [182]
Three independent chemogenomic screening studies identified structurally diverse molecular glue degraders of cyclin K.
“With regard to the second novel class of agents, three independent chemogenomic screening studies resulted in the identification of structurally diverse molecular glue degraders of cyclin K.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [182]
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References 31 · Cited by 123
- Authors
- Ting, T. C., Goralski, M., Klein, K., Wang, B., Kim, J., Xie, Y., & Nijhawan, D.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Harold C. Simmons Comprehensive Cancer Center (US)
- Corresponding author
- Nijhawan, Deepak
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2019-11
- Volume
- 29
- Issue
- 6
- Pages
- 1499-1510.e6
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC7950731
- OpenAlex
- W2987448722
- Cited by
- 123
- References
- 31
- Citations by year
- 2026: 9 · 2025: 17 · 2024: 21 · 2023: 22 · 2022: 21 · 2021: 16 · 2020: 17
- FWCI
- 4.47
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- McKnight Foundation
- National Cancer Institute (R37CA226771, RO1CA217333, RBM23, RBM39 G268V, HCT116)
- Welch Foundation (I-1879)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- indisulam, arylsulfonamides, RBM39, E3 ubiquitin ligase, protein degradation, ubiquitination, splicing factors, intron retention, exon skipping, aberrant splicing, selective degradation
- MeSH terms
- RNA Recognition Motif Proteins, Protein Domains, Humans, Lysine, Mutation, Protein Binding, RNA Splicing, Sulfonamides, Mutagenesis, RNA-Binding Proteins, Ubiquitin-Protein Ligases, Cell Line, Tumor, Proteasome Endopeptidase Complex, Intracellular Signaling Peptides and Proteins, Receptors, Interleukin-17, Ubiquitination
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