Unidentified
Ontology highlight
ABSTRACT:
PROVIDER: PRJDB19429 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| DRR675459_1.fastq.gz | Fastqsanger.gz | |||
| DRR675459_2.fastq.gz | Fastqsanger.gz | |||
| DRR675460_1.fastq.gz | Fastqsanger.gz | |||
| DRR675460_2.fastq.gz | Fastqsanger.gz | |||
| DRR675461_1.fastq.gz | Fastqsanger.gz |
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Project description:Development of drug discovery platform based on targeted protein degradation (KAP230657)
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Project description:Targeted protein degradation is a groundbreaking modality in drug discovery ; however, the regulatory mechanisms are still not fully understood. Here, we identify cellular signaling pathways that modulate the targeted degradation of the anticancer target BRD4 and related hard-to-degrade targets BRD2/3 induced by CRL2VHL- or CRL4CRBN -based PROTACs. The chemicals identified as degradation enhancers include inhibitors of cellular signaling pathways such as poly-ADP ribosylation (PARG inhibitor PDD00017273), unfolded protein response (PERK inhibitor GSK2606414), and protein stabilization (HSP90 inhibitor luminespib). Mechanistically, PARG inhibition promotes TRIP12-mediated K29/K48-linked branched ubiquitylation of BRD4 by facilitating chromatin dissociation of BRD4 and formation of the BRD4–PROTAC–CRL2VHL ternary complex; by contrast, HSP90 inhibition promotes BRD4 degradation after the ubiquitylation step. Consequently, these signal inhibitors sensitize cells to the PROTAC-induced apoptosis. These results suggest that various cell-intrinsic signaling pathways spontaneously counteract chemically induced target degradation at multiple steps, which could be liberated by specific inhibitors.
2024-05-17 | GSE262938 | GEO
Project description:Targeted protein degradation (TPD) refers to the use of small molecules to induce ubiquitin-dependent degradation of proteins. These degrader molecules are of great interest in drug development as they can address previously inaccessible targets. However, degrader discovery and optimization remains an inefficient and empirical process due to a lack of understanding of the key molecular events required to successfully induce target degradation. Here we used a time-course experiment to assess the transcriptional response to rapid pan-Kinase degradation.
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Project description:Establishment of customized drug efficacy assessment platform based on the comparative analysis of primate degenerative brain (KAP210053)
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Project description:Establishment of customized drug efficacy assessment platform based on the comparative analysis of primate degenerative brain (KAP230661)
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Project description:Establishment of customized drug efficacy assessment platform based on the comparative analysis of primate degenerative brain (KAP220488)
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Project description:Molecular tether-mediated extracellular targeted protein degradation (ePTD) emerges as a promising drug modality. The existing strategies for ePTD have exploited several membrane degrader proteins. However, the current panel of ePTD degraders clearly needs to be expanded, as a given degrader may present tissue-dependent expression and activity. Based on screening of >50 receptors on endocytic rates and on their tissue distribution, we established a resource of potential endocytic carriers that may mediate effective ePTD. We subsequently introduced an adaptable design to assemble “Selected endocytic carrier-targeting chimera (SecTAC)” based on bispecific antibody constructs. The resultant modular chimeras, by co-opting newly identified degraders, directed efficient internalization of extracellular protein cargoes (or nucleic acids). Importantly, shaped by the availability of the corresponding endocytic carrier, the output of a SecTAC could present cell subset selectivity. We also validated the therapeutic potential of SecTAC agents for targeting several cell membrane proteins in tumor cells and primary T cells. Furthermore, we adapted the platform to establish multi-cargo tethers that triggered simultaneous degradation of two cell surface proteins in primary T cells. Taken together, our SecTAC platform has laid the foundation for development of preclinical drug candidates capable of inducing extracellular and membrane target degradation in desirable population of cells.
2024-04-13 | GSE263462 | GEO
Project description:Targeted protein degradation is a groundbreaking modality in drug discovery ; however, further improvement of the degradation efficacy is demanded. Here, we identify small molecules that enhance the targeted degradation of the anticancer target BRD4 and related hard-to-degrade targets BRD2/3 induced by CRL2VHL- or CRL4CRBN -based PROTACs. The chemicals include inhibitors of cellular signaling pathways such as poly-ADP ribosylation (PARG inhibitor PDD00017273), unfolded protein response (PERK inhibitor GSK2606414), and protein stabilization (HSP90 inhibitor luminespib). Mechanistically, PARG inhibition promotes TRIP12-mediated K29/K48-linked branched ubiquitylation of BRD4 by facilitating chromatin dissociation of BRD4 and formation of the BRD4–PROTAC– CRL2VHL ternary complex; by contrast, HSP90 inhibition promotes BRD4 degradation after the ubiquitylation step. Consequently, these signal inhibitors sensitize cells to the PROTAC-induced apoptosis. Combining the treatment with these chemicals further increases the efficacy of a highly potent PROTAC, SIM1. We propose that various cell intrinsic signaling pathways spontaneously counteract chemically induced target degradation, which can be liberated by specific inhibitors.
2024-05-17 | GSE243615 | GEO
Project description: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) represented by 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 CAPER-alpha via DCAF15-DDB1-CUL4 CRL4-DCAF15 mediated ubiquitination in human cancer cell lines. Both CRISPR/Cas9-based knockout of DCAF15 and a single amino acid substitution of CAPER-alpha conferred resistance against sulfonamide-induced CAPER-alpha degradation and cell-growth inhibition. Thus, the these sulfonamides represent selective chemical probes for disrupting CAPER-alpha function and designate DCAFs as promising drug targets for promoting selective protein degradation in cancer therapy.
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Project description:Targeted protein degradation (TPD) using the ubiquitin proteasome system (UPS) is a rapidly growing drug discovery modality to eliminate pathogenic proteins. Strategies for TPD have focused on heterobifunctional degraders that often suffer from poor drug-like properties, and molecular glues that rely on serendipitous discovery. Monovalent direct degraders represent an alternative approach, in which small molecules bind to a target protein and induce degradation of that protein through the recruitment of an E3 ligase complex. Using an ultra-high throughput cell-based screening platform, degraders of the bromodomain extra-terminal (BET) protein BRD4 were identified and optimized to yield a lead compound, PLX-3618. In this paper, we demonstrate that PLX-3618 elicited UPS-mediated selective degradation of BRD4, resulting in potent anti-tumor activity in vitro and in vivo. Characterization of the degradation mechanism identified DCAF11 as the E3 ligase required for PLX-3618-mediated degradation of BRD4. Protein-protein interaction studies verified a BRD4:PLX-3618:DCAF11 ternary complex, and mutational studies provided further insights into the DCAF11-mediated degradation mechanism. Collectively, these results demonstrate the discovery and characterization of a novel small molecule that selectively degrades BRD4 through the recruitment of the E3 substrate receptor, DCAF11, and promotes potent anti-tumor activity in vivo.
2024-06-10 | MSV000094973 | MassIVE