RUNX1 knockdown and BET protein proteolysis targeting chimera (PROTAC) exerts potent lethal activity against mtRUNX1 AML cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA488623 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7770480_1.fastq.gz | Fastqsanger.gz | |||
| SRR7770480_2.fastq.gz | Fastqsanger.gz | |||
| SRR7770490_1.fastq.gz | Fastqsanger.gz | |||
| SRR7770490_2.fastq.gz | Fastqsanger.gz | |||
| SRR7770481_1.fastq.gz | Fastqsanger.gz |
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Project description:Bromodomain extraterminal protein (BETP) inhibitors transcriptionally repress oncoproteins which undermines the growth and survival of AML cells. However, BETi treatment causes accumulation of BETPs, associated with reversible binding and incomplete inhibition of BRD4, which potentially compromises the activity of BETi in AML cells. Unlike BETi, BET-PROTAC (proteolysis-targeting chimera) ARV-825 recruits and utilize an E3-ubiquitin ligase to effectively degrade BETPs in AML cells. BET-PROTACs induce more apoptosis than BETi of mtRUNX1 AML cells. BET-PROTAC treatment induced more perturbations in the mRNA and protein expressions than BETi. It was noted that treatment with BETi or BET-PROTAC caused significant and sustained depletion of RUNX1 in AML cells. We also determined the effects of global depletion of RUNX1 in mtRUNX1 expressing AML OCI-AML5 cells. We observed an overlap in the signature of RUNX1 knockdown by shRNA with that of OTX015 and ARV-825 in OCI-AML5 cells.
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Project description:Bromodomain extraterminal protein (BETP) inhibitors transcriptionally repress oncoproteins and NFkB target genes, which undermines the growth and survival of MCL cells. However, BETi treatment causes accumulation of BETPs, associated with reversible binding and incomplete inhibition of BRD4, which potentially compromises the activity of BETi in MCL cells. Unlike BETi, BET-PROTACs (proteolysis-targeting chimera) ARV-825 and ARV-771 (Arvinas, Inc.) recruit and utilize an E3-ubiquitin ligase to effectively degrade BETPs in MCL cells. BET-PROTACs induce more apoptosis than BETi of MCL cells, including those resistant to ibrutinib. BET-PROTAC treatment induced more perturbations in the mRNA and protein expressions than BETi, with depletion of c-Myc, CDK4, cyclin D1, and the NFkB transcriptional targets Bcl-xL, XIAP and BTK, while inducing the level of HEXIM1, NOXA and CDKN1A/p21. Treatment with ARV-771, which possesses superior pharmacological properties compared to ARV-825, inhibited the in vivo growth and induced greater survival improvement than the BETi OTX015 of immune-depleted mice engrafted with MCL cells. Co-treatment of ARV-771 with ibrutinib or the BCL2-antagonist venetoclax or CDK4/6 inhibitor palbociclib synergistically induced apoptosis of MCL cells. These studies highlight promising and superior pre-clinical activity of BET-PROTAC than BETi, requiring further in vivo evaluation of BET-PROTAC as a therapy for ibrutinib-sensitive or resistant MCL.
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Project description:The PROTAC (proteolysis-targeting chimera) ARV-825 recruits bromodomain and extraterminal (BET) proteins to the E3 ubiquitin ligase cereblon, leading to degradation of BET proteins, including BRD4. Whereas the BET-protein inhibitor (BETi) OTX015 caused accumulation of BRD4, treatment with equimolar concentrations of ARV-825 caused sustained and profound depletion (>90%) of BRD4 and induced significantly more apoptosis in cultured and patient-derived (PD) CD34+ post-MPN sAML cells, while relatively sparing the CD34+ normal hematopoietic progenitor cells. RNA-Seq, Reversed Phase Protein Array and mass cytometry ‘CyTOF’ analyses demonstrated that ARV-825 caused greater perturbations in mRNA and protein expressions than OTX015 in sAML cells. Specifically, compared to OTX015, ARV-825 treatment caused more robust and sustained depletion of c-Myc, CDK4/6, JAK2, pSTAT3/5, PIM1 and Bcl-xL, while increasing the levels of p21 and p27. Compared to OTX015, PROTAC ARV-771 treatment caused greater reduction in leukemia burden and further improved survival of NSG mice engrafted with luciferase-expressing HEL92.1.7 cells. Co-treatment with ARV-825 and JAK inhibitor ruxolitinib was synergistically lethal against the established and PD-CD34+ sAML cells. Notably, ARV-825 induced high levels of apoptosis in the in vitro generated ruxolitinib-persister or ruxolitinib-resistant sAML cells. These findings strongly support the in vivo testing of the BRD4-PROTAC based combinations against post-MPN sAML.
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Project description:Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a critical stress sentinel that co- ordinates cell survival, inflammation, and immunogenic cell death (ICD). Although the catalytic function of RIPK1 is required to trigger cell death, its non-catalytic scaffold function mediates strong pro-survival signaling. Accordingly, cancer cells can hijack RIPK1 to block necroptosis and evade immune detection. We generated a small-molecule proteolysis-targeting chimera (PROTAC) that selectively degraded human and murine RIPK1. PROTAC-mediated depletion of RIPK1 deregulated TNFR1 and TLR3/4 signaling hubs, accentuating the output of NF-kB, MAPK, and IFN signaling. Additionally, RIPK1 degradation simultaneously promoted RIPK3 activation and necroptosis induction. We further demonstrated that RIPK1 degradation enhanced the immunostimulatory effects of radio- and immunotherapy by sensitizing cancer cells to treat- ment-induced TNF and interferons. This promoted ICD, antitumor immunity, and durable treatment responses. Consequently, targeting RIPK1 by PROTACs emerges as a promising approach to overcome radio- or immunotherapy resistance and enhance anticancer therapies.
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Project description:The RAF family kinases function in the RAS-ERK pathway to transmit signals from activated RAS to the downstream kinases MEK and ERK. This pathway regulates cell proliferation, differentiation, and survival enabling mutations in RAS and RAF to act as potent drivers of human cancers. Drugs targeting the prevalent oncogenic mutant BRAFV600E have shown great efficacy in the clinic but long-term effectiveness is limited by resistance mechanisms that often exploit the dimerization-dependent process by which RAF kinases are activated. Here, we investigated a proteolysis targeting chimera (PROTAC) approach to BRAF inhibition. The most effective PROTAC termed P4B displayed superior specificity and inhibitory properties relative to non-PROTAC controls in BRAFV600E cell lines. In addition, P4B displayed utility in two cell lines harboring alternate BRAF mutations that impart resistance to conventional BRAF inhibitors. This work provides a rationale for optimizing the drug-like properties of P4B to enable proof of concept studies in vivo.
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Project description:MDM2 inhibitor remarkably induced biomineralization in hDPSCs but it remained the problem that p53 activation is insufficient due to MDM2-p53 autoregulatory feedback loop. To overcome the limitation of the MDM2 inhibitors, we applied proteolysis targeting chimera (PROTAC), a technology that degrades a protein of interest (POI) by intracellular ubiquitin-proteasome system. Hence, we propose a strategy to induce hard tissue regeneration by MDM2-targeting PROTAC technology. We selected Nutlin-3 of POI ligand among various MDM2 inhibitors based on the screening process, and the selected CRBN of E3 ligase ligand. The MDM2-PROTAC synthesis platform was designed by each ligand combination. By performing the degradation test for selected compounds, we evaluated the characteristics of the developed MDM2 PROTAC such as the maximal degradation concentration (DCmax), the half of maximal degradation concentration (DC50), and half-lifetime. To investigate gene expression profiling of MDM2-targeting small molecules, we conducted RNA-sequencing under MDM2 PROTAC and Nutlin-3 (POI ligand) treated conditions. We not only confirmed a robust effect on biomineralization by MDM2-targeting small molecules but also demonstrated the potent osteogenic differentiation ability of MDM2 PROTAC when compared to an MDM2 inhibitor. MDM2-PROTAC significantly increased mRNA levels of osteogenic differentiation marker genes. Also, the significant bone generation effect of MDM2 PROTAC was validated in an ovariectomy (OVX)-induced osteoporosis animal model. Through these results, it is expected that a new therapeutic modality for hard tissue regeneration will be possible, and the application range of the PROTAC system can be expanded.
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Project description:Proteolysis Targeting Chimeras (PROTACs) are attractive therapeutic modalities for degrading disease-causing proteins. While many PROTACs have been developed for numerous protein targets, current small-molecule PROTAC approaches cannot target undruggable proteins that do not have small-molecule binders. Here, we present a novel PROTAC approach, termed bridged PROTAC, which utilizes a small-molecule binder of the target protein's binding partner to recruit the protein complex into close proximity with an E3 ubiquitin ligase to target undruggable proteins. Applying this bridged PROTAC strategy, we discovered MS28, the first-in-class degrader of cyclin D1, which lacks a small-molecule binder. MS28 effectively degrades cyclin D1, with faster degradation kinetics and superior degradation efficiency than CDK4/6, through recruiting the CDK4/6-cyclin D1 complex to the von Hippel-Lindau E3 ligase. MS28 also suppressed the proliferation of cancer cells more effectively than CDK4/6 inhibitors and degraders. Altogether, the bridged PROTAC strategy could provide a generalizable platform for targeting undruggable proteins.
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