CAPE
- Known as:
- CAPE
- Catalog number:
- SIH-263-50MG
- Product Quantity:
- Inhibitor
- Category:
- -
- Supplier:
- Stressmarq
- Gene target:
- CAPE
Related genes to: CAPE
- Gene:
- RBM23 NIH gene
- Name:
- RNA binding motif protein 23
- Previous symbol:
- RNPC4
- Synonyms:
- FLJ10482, CAPERbeta
- Chromosome:
- 14q11.2
- Locus Type:
- gene with protein product
- Date approved:
- 2002-12-18
- Date modifiied:
- 2016-10-25
- Gene:
- RBM39 NIH gene
- Name:
- RNA binding motif protein 39
- Previous symbol:
- RNPC2
- Synonyms:
- CC1.3, HCC1, CAPER, fSAP59, CAPERalpha
- Chromosome:
- 20q11.22
- Locus Type:
- gene with protein product
- Date approved:
- 2001-06-21
- Date modifiied:
- 2014-11-19
Related products to: CAPE
Related articles to: CAPE
- Indisulam, a DCAF15-based molecular glue degrader, induces widespread proteome changes with implications for cell division and chromosome segregation. While RBM39 and RBM23 are two well-characterized indisulam neo-substrates, additional targets likely exist. To identify those degradation targets, we applied a network-based approach to prioritize novel neo-substrates from large-scale omics data. Our approach integrates proteome-wide expression measurements with information from publicly accessible databases into a multilayer heterogeneous network. Utilizing a Random Walk with Restart algorithm, we identified a preliminary list of 30 neo-substrates. These proteins are likely interactors with DCAF15 in the presence of indisulam and are subject to subsequent degradation. Experimental validation of hits from the shortlisted candidates confirmed their degradation in a proteasome-dependent manner, supporting their identification as potential novel indisulam neo-substrates. Our work employs established network resources and analytical methods to effectively identify direct targets of the indisulam molecular glue degrader. This approach is readily adaptable for exploring novel targets across other molecular glue systems, enhancing its applicability and value to the drug discovery community. - Source: PubMed
Publication date: 2025/12/01
Jarnuczak Andrew FYogev OrliAndres AngeloAshenden Stephanie KYe ChengPachl FionaZhang AndrewCuomo Maria EmanuelaJin Meizhong - Targeted protein degradation (TPD) is a new pharmacology based on small-molecule degraders that induce proximity between a protein of interest (POI) and an E3 ubiquitin ligase. Of the approximately 600 E3s encoded in the human genome, only around 2% can be co-opted with degraders. This underrepresentation is caused by a paucity of discovery approaches to identify degraders for defined E3s. This hampers a rational expansion of the druggable proteome and stymies critical advancements in the field, such as tissue- and cell-specific degradation. Here, we focus on dynamic NEDD8 conjugation, a post-translational, regulatory circuit that controls the activity of 250 cullin RING E3 ligases (CRLs). Leveraging this regulatory layer enabled us to develop a scalable assay to identify compounds that alter the interactome of an E3 of interest by tracing their abundance after pharmacologically induced auto-degradation. Initial validation studies are performed for CRBN and VHL, but proteomics studies indicate broad applicability for many CRLs. Among amenable ligases, we select CRL for a proof-of-concept screen, leading to the identification of a novel DCAF15-dependent molecular glue degrader inducing the degradation of RBM23 and RBM39. Together, this strategy empowers the scalable identification of degraders specific to a ligase of interest. - Source: PubMed
Publication date: 2023/01/05
Hanzl AlexanderBarone EleonoraBauer SophieYue HongNowak Radosław PHahn ElisaPankevich Eugenia VKoren AnnaKubicek StefanFischer Eric SWinter Georg E - Aryl hydrocarbon receptor nuclear translocator (ARNT) plays an essential role in maintaining cellular homeostasis in response to environmental stress. Under conditions of hypoxia or xenobiotic exposure, ARNT regulates the subset of genes involved in adaptive responses, by forming heterodimers with hypoxia-inducible transcription factors (HIF1α and HIF2α) or aryl hydrocarbon receptor (AhR). Here, we have shown that ARNT interacts with DDB1 and CUL4-associated factor 15 (DCAF15), and the aryl sulfonamides, indisulam and E7820, induce its proteasomal degradation through Cullin-RING finger ligase 4 containing DCAF15 (CRL4) E3 ligase. Moreover, the two known neo-substrates of aryl sulfonamide, RNA-binding motif protein 39 (RBM39) and RNA-binding motif protein 23 (RBM23), are not required for ARNT degradation. In line with this finding, aryl sulfonamides inhibited the transcriptional activities of HIFs and AhR associated with ARNT. Our results collectively support novel regulatory roles of aryl sulfonamides in both hypoxic and xenobiotic responses. - Source: PubMed
Kim Sung AhJo Seung-HyunCho Jin HwaYu Min YeongShin Ho-ChulKim Jung-AePark Sung GooPark Byoung ChulKim SunhongKim Jeong-Hoon - The anticancer agent indisulam inhibits cell proliferation by causing degradation of RBM39, an essential mRNA splicing factor. Indisulam promotes an interaction between RBM39 and the DCAF15 E3 ligase substrate receptor, leading to RBM39 ubiquitination and proteasome-mediated degradation. To delineate the precise mechanism by which indisulam mediates the DCAF15-RBM39 interaction, we solved the DCAF15-DDB1-DDA1-indisulam-RBM39(RRM2) complex structure to a resolution of 2.3 Å. DCAF15 has a distinct topology that embraces the RBM39(RRM2) domain largely via non-polar interactions, and indisulam binds between DCAF15 and RBM39(RRM2), coordinating additional interactions between the two proteins. Studies with RBM39 point mutants and indisulam analogs validated the structural model and defined the RBM39 α-helical degron motif. The degron is found only in RBM23 and RBM39, and only these proteins were detectably downregulated in indisulam-treated HCT116 cells. This work further explains how indisulam induces RBM39 degradation and defines the challenge of harnessing DCAF15 to degrade additional targets. - Source: PubMed
Publication date: 2019/12/09
Bussiere Dirksen EXie LiliSrinivas HonnappaShu WeiBurke AshleyBe CelineZhao JunpingGodbole AdarshKing DanKarki Rajeshri GHornak ViktorXu FangminCobb JenniferCarte NathalieFrank Andreas OFrommlet AlexandraGraff PatrickKnapp MarkFazal AleemOkram BarunJiang SongchunMichellys Pierre-YvesBeckwith RohanVoshol HansWiesmann ChristianSolomon Jonathan MPaulk Joshiawa - 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. - Source: PubMed
Ting Tabitha CGoralski MariaKlein KatherineWang BaiyunKim JiwoongXie YangNijhawan Deepak