Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15

Faust, Thomas W.; Yoon, Hojong; Nowak, Radosław P.; Donovan, Katherine A.; Li, Zhengnian; Cai, Quan; Eleuteri, Nicholas A.; Zhang, Tinghu; Gray, Nathanael S.; Fischer, Eric S.

doi:10.1101/738534

Cited by 9 publications

(16 citation statements)

References 41 publications

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“…Treating this cell line with the ArSulfs showed no degradation of RBM23 in TMT-proteomics and confirmed the DCAF15 dependency ( Figure S1B). In line with recent reports, [15,17] these results suggest that DCAF15/ArSulf/RBM39 (or RBM23) interaction strictly requires the sequence of the RRM2 domain present in RBM39 and RBM23, confirming ArSulfs as highly selective degraders. Consistent with previous observations [23], we also observed reduced protein levels of MCL1 in the leukemia cell line Mv4;11.…”

Section: Assessing Proteome-wide Selectivity Of the Dcaf15/arsulf/rbmsupporting

confidence: 92%

“…[13,14] Several structural studies have since shown that ArSulfs create a new protein-protein interaction by simultaneously binding both DCAF15 and the splicing factor RBM39 ( Figure 1A). [15][16][17] Since DCAF15 is an E3 ligase adaptor protein, this binding makes RBM39 susceptible to ubiquitination and subsequent degradation in a mechanism that is reminiscent of the more established immunomodulatory drugs (IMiDs) thalidomide and lenalidomide. [18,19] The ArSulfs chloroquinoxaline sulfonamide (CQS), tasisulam, and E7820 ( Figure 1B) are structurally related to indisulam and have all been shown to degrade RBM39.…”

Section: Introductionmentioning

confidence: 99%

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Arylsulfonamide mediated RBM39 degradation causes aberrant splicing of mitotic kinesins

Coomar¹,

Penson

Schwaller

et al. 2021

Preprint

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Certain arylsulfonamides (ArSulfs) induce an interaction between the E3 ligase substrate adaptor DCAF15 and the critical splicing factor RBM39, ultimately causing its degradation. Although molecules like the ArSulfs, which interfere with splicing decisions, are exciting potential medicines, the molecular glue mechanism of RBM39 degradation introduces complex pleiotropic effects that are difficult to untangle. For example, DCAF15 inhibition, RBM39 degradation, and the downstream proteome effects of splicing changes will all cause different yet overlaid effects. As such the precise cell-killing mechanism by RBM39 loss is largely unknown. By overlaying transcriptome and proteome datasets, we distinguish transcriptional from post-transcriptional effects, pinpointing those proteins most impacted by splicing changes. Our proteomic profiling of several ArSulfs suggests a selective DCAF15/ArylSulf/RBM39RRM2 interaction with a narrow degradation profile. We identify two mitotic kinesin motor proteins that are aberrantly spliced upon RBM39 degradation, and we demonstrate that these are likely contributors to the antiproliferative activity of ArSulfs.

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Section: Assessing Proteome-wide Selectivity Of the Dcaf15/arsulf/rbmsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Arylsulfonamide mediated RBM39 degradation causes aberrant splicing of mitotic kinesins

Coomar¹,

Penson

Schwaller

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…The overall structure of CPSF160-WDR33 is similar to that of the DDB1-DDB2 complex that is important for sensing and repairing DNA damage [70][71][72]. DDB1 can also interact with other proteins using its three β-propeller domains [73][74][75][76][77]. The BPA and BPC domains and the CTD of CPSF160 are involved in many interactions in the structures determined so far.…”

Section: Cpsf160-wdr33 Is the Core Of The Canonical Machinerymentioning

confidence: 89%

Recent molecular insights into canonical pre-mRNA 3’-end processing

2020

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The majority of eukaryotic messenger RNA precursors (pre-mRNAs) undergo cleavage and polyadenylation at their 3′ end. This canonical 3′-end processing depends on sequence elements in the pre-mRNA as well as a mega-dalton protein machinery. The cleavage site in mammalian pre-mRNAs is located between an upstream poly(A) signal, most frequently an AAUAAA hexamer, and a GU-rich downstream sequence element. This review will summarize recent advances from the studies on this canonical 3′-end processing machinery. They have revealed the molecular mechanism for the recognition of the poly(A) signal and provided the first glimpse into the overall architecture of the machinery. The studies also show that the machinery is highly dynamic conformationally, and extensive rearrangements are necessary for its activation. Inhibitors targeting the active site of the CPSF73 nuclease of this machinery have anti-cancer, anti-inflammatory and anti-protozoal effects, indicating that CPSF73 and pre-mRNA 3′-end processing in general are attractive targets for drug discovery.

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“…In 2019, three independent groups released cocrystal structures of CAPERα–sulfonamide–DCAF15–DDB1–DDA1 multimeric complexes and confirmed that sulfonamides induce formation of the complexes as a molecular glue. 73–75 Their structural information could help to further optimize sulfonamides using structure-based drug design and leverage them as DCAF15 ligands for PROTAC design. Until recently, however, it has remained challenging to develop indisulam-based DCAF15-recruiting PROTACs, 76,77 most likely because of the weak binding affinities of these compounds to DCAF15 alone, or perhaps due to unsuitable orientation between the binding pocket of sulfonamides and the RING domain of CUL4.…”

Section: Introductionmentioning

confidence: 99%

E3 Ligase Ligands for PROTACs: How They Were Found and How to Discover New Ones

2021

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Bifunctional degrader molecules, also called proteolysis-targeting chimeras (PROTACs), are a new modality of chemical tools and potential therapeutics to understand and treat human disease. A required PROTAC component is a ligand binding to an E3 ubiquitin ligase, which is then joined to another ligand binding to a protein to be degraded via the ubiquitin–proteasome system. The advent of nonpeptidic small-molecule E3 ligase ligands, notably for von Hippel–Lindau (VHL) and cereblon (CRBN), revolutionized the field and ushered in the design of drug-like PROTACs with potent and selective degradation activity. A first wave of PROTAC drugs are now undergoing clinical development in cancer, and the field is seeking to extend the repertoire of chemistries that allow hijacking new E3 ligases to improve the scope of targeted protein degradation. Here, we briefly review how traditional E3 ligase ligands were discovered, and then outline approaches and ligands that have been recently used to discover new E3 ligases for PROTACs. We will then take an outlook at current and future strategies undertaken that invoke either target-based screening or phenotypic-based approaches, including the use of DNA-encoded libraries (DELs), display technologies and cyclic peptides, smaller molecular glue degraders, and covalent warhead ligands. These approaches are ripe for expanding the chemical space of PROTACs and usher in the advent of other emerging bifunctional modalities of proximity-based pharmacology.

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Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15

Cited by 9 publications

References 41 publications

Arylsulfonamide mediated RBM39 degradation causes aberrant splicing of mitotic kinesins

Arylsulfonamide mediated RBM39 degradation causes aberrant splicing of mitotic kinesins

Recent molecular insights into canonical pre-mRNA 3’-end processing

E3 Ligase Ligands for PROTACs: How They Were Found and How to Discover New Ones

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