Piperlongumine (PL) conjugates induce targeted protein degradation
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PROVIDER: PRJNA851461 | ENA |
REPOSITORIES: ENA
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Project description:PROteolysis Targeting Chimeras (PROTACs) are bifunctional molecules that degrade target proteins through recruiting E3 ligases. However, their application is limited in part because few E3 ligases can be recruited by known E3 ligase ligands. In this study, we identified piperlongumine (PL), a natural product, as a covalent E3 ligase recruiter, which induces CDK9 degradation when it is conjugated with SNS032, a CDK9 inhibitor. The lead conjugate 955 can potently degrade CDK9 in a ubiquitin-proteasome-dependent manner and is much more potent than SNS-032 against various tumor cells in vitro. Mechanistically, we identified KEAP1 as the E3 ligase recruited by 955 to degrade CDK9 through a TurboID-based proteomics study, which was further confirmed by KEAP1 knockout and the nanoBRET ternary complex formation assay. In addition, PL-Ceritinib conjugate can degrade EML4-ALK fusion oncoprotein, suggesting that PL may have a broader application as a covalent E3 ligase ligand in targeted protein degradation.
2022-06-26 | GSE206612 | GEO
Project description:PROteolysis Targeting Chimeras (PROTACs) are bifunctional molecules that degrade target proteins through recruiting E3 ligases. However, their application is limited in part because few E3 ligases can be recruited by known E3 ligase ligands. In this study, we identified piperlongumine (PL), a natural product, as a covalent E3 ligase recruiter, which induces CDK9 degradation when it is conjugated with SNS-032, a CDK9 inhibitor. To evaluate the specificity of the PL-SNS-032 lead conjugate named 955, TMT-based proteomics were conducted to compare 955 with its warhead SNS-032 in MOLT4 cells. As expected, cells exhibited a significant reduction of CDK9 after treatment with 0.1 µM 955 for 1 h and 6 h while treatment with 1 µM SNS-032 for 6 h had no significant effect on CDK9. Interestingly, 955, but not SNS-032, can also potently degrade CDK10.
2024-05-24 | PXD039385 | Pride
Project description:Previous work has led us to examine the differences in the choroid plexus function in B10.pl WT mice versus B10.PL RAG-/- mice. We believe that there is a difference between those that are normal functioning and those that are lymphocyte deficient. To determine the gene expression profile of the choroid plexus in wild type mice as compared to those that are lymphocyte deficient. We hypothesize that there is altered expression in the genes that mediate cellular adhesion in choroid plexus from wild type mice as compared to those that are lymphocyte deficient. 8-10 week old animals (age and sex matched) were injected with Evan's blue post anesthetization. After waiting an hour the animals were euthanized and their brains were extracted and placed in RNALater for 24 hours. The brains were then sliced sagitally
2008-06-20 | E-GEOD-11443 | biostudies-arrayexpress
Project description: Not available
| S-EPMC7309268 | biostudies-literature
Project description:To investigate the effect of PL on gene expression, we have employed whole genome microarray expression profiling as a discovery platform to identify genes with the potential to suppress the cell proliferation of OSCC cell lines. SAS and HSC-3 cells were treated with PL (5 μmol/L) for 4 h in vitro.
2021-12-24 | GSE188168 | GEO
Project description:SPT6 is both, an important histone chaperone and POL2 elongation factor but its primary role on transcription in mammalian cells remains open, as no acute depletion system is available. We used targeted protein degradation to rapidly deplete SPT6 and analyzed defects in POL2 behavior by a multi-omics approach and estimated POL2 processivity, elongation rates and termination and compared it to gene transcription. Our data indicate that SPT6 is a crucial factor for POL2 elongation. Unexpectedly, SPT6 has also a vital role in POL2 termination, as acute depletion induces POL2 read through at most protein coding genes. In contrast, acute depletion did not induce spurious intragenic initiation, while this behavior can be induced by long-term depletion of SPT6 and can therefore be attributed to its function as a histone chaperone. In conclusion, targeted protein degradation of SPT6 allows the kinetic discrimination of its function as a histone chaperone and POL2 elongation factor.
2021-06-23 | GSE162264 | GEO
Project description:Using this approach the dasatinib-oligonucleotide conjugates was applied to planar arrays of >9,000 human proteins spotted in two technical replicates. All proteins in the commercially available ProtoArray® Human Protein MicroArray (Thermo Fisher Scientific) have been purified and arrayed under native conditions to allow such studies. We adopted this format for investigation of the binding profiles of the drug-oligonucleotide conjugates. Fluorophore-labeled drugs have previously been used to measure binding in protein arrays. The oligonucleotide-conjugated constructed allowed for locally amplified detection via RCA. Circularizing oligonucleotides (padlock probes) were designed with 5’ and 3’ ends complementary to adjacent segments of the oligonucleotides conjugated to the drug molecules. Once converted to oligonucleotide circles by ligation, the probes were replicated through localized RCA, primed by the drug-conjugated oligonucleotides, and visualized using fluorescence-labeled hybridization probes to the repeated sequence of the RCA products. RCA offers a signal enhancement of several hundredfold over singly fluorophore labeled compounds, permitting visualization of even single bound drug probes
2022-09-12 | E-MTAB-12192 | biostudies-arrayexpress
Project description:Previous work has led us to examine the differences in the choroid plexus function in B10.pl WT mice versus B10.PL RAG-/- mice. We believe that there is a difference between those that are normal functioning and those that are lymphocyte deficient. To determine the gene expression profile of the choroid plexus in wild type mice as compared to those that are lymphocyte deficient. We hypothesize that there is altered expression in the genes that mediate cellular adhesion in choroid plexus from wild type mice as compared to those that are lymphocyte deficient. 8-10 week old animals (age and sex matched) were injected with Evan's blue post anesthetization. After waiting an hour the animals were euthanized and their brains were extracted and placed in RNALater for 24 hours. The brains were then sliced sagitally Keywords: RAG mutant, choroid plexus
2008-05-17 | GSE11443 | GEO
Project description:Objectives Pyrrolobenzodiazepine (PBD) dimers, tethered through inert propyldioxy or pentyldioxy linkers, possess potent bactericidal activity against a range of Gram-positive bacteria by virtue of their capacity to cross-link duplex DNA in sequence-selective fashion. Here we attempt to improve the antibacterial activity and cytotoxicity profile of PBD-containing conjugates by extension of dimer linkers and replacement of one PBD unit with phenyl-substituted or benzo-fused heterocycles that facilitate non-covalent interactions with duplex DNA. Methods DNase I footprinting was used to identify high-affinity DNA binding sites. A staphylococcal gene microarray was used to assess epidemic methicillin-resistant Staphylococcus aureus 16 phenotypes induced by PBD conjugates. Molecular dynamics simulations were employed to investigate the accommodation of compounds within the DNA helix. Results Increasing the length of the linker in PBD dimers led to a progressive reduction in antibacterial activity, but not in their cytotoxic capacity. Complex patterns of DNA binding were noted for extended PBD dimers. Modelling of DNA strand cross-linking by PBD dimers indicated distortion of the helix. A majority (26 of 43) of PBD-biaryl conjugates possessed potent antibacterial activity with little or no helical distortion and a more favourable cytotoxicity profile. Bactericidal activity of PBD-biaryl conjugates was determined by inability to excise covalently bound drug molecules from bacterial duplex DNA. Conclusions PBD-biaryl conjugates have a superior antibacterial profile compared with PBD dimers such as ELB-21. We have identified six PBD-biaryl conjugates as potential drug development candidates. [Data is also available from http://bugs.sgul.ac.uk/E-BUGS-118]
2012-04-17 | E-BUGS-118 | biostudies-arrayexpress
Project description:Geobacter sulfurreducens strain:PL Genome sequencing
| PRJNA719736 | ENA