- |||||||||| Ibrance (palbociclib) / Pfizer, UNC1999 - University of North Carolina / Chapel Hill
Journal: Ezh2 Delays Activation of Differentiation Genes During Normal Cerebellar Granule Neuron Development and in Medulloblastoma. (Pubmed Central) - Nov 28, 2024
Similarly, in MB cells, neuronal differentiation could be induced by preventing H3K27me3 modifications using an Ezh2 inhibitor (UNC1999), but only when UNC1999 was combined with forced cell cycle exit driven by a CDK4/6 inhibitor (Palbociclib). Ezh2 emerges as a powerful restraint upon post-mitotic differentiation during normal GNP development and combination of Ezh2 inhibition with cell cycle exit leads to MB cell differentiation.
- |||||||||| UNC1999 - University of North Carolina / Chapel Hill, Tazverik (tazemetostat) / Ipsen
NOVEL EPIGENETIC MECHANISMS DRIVE AGGRESSIVE OSTEOSARCOMA PATHOGENESIS AND DRUG RESISTANCE () - Nov 9, 2024 - Abstract #CTOS2024CTOS_319;
EZHIP stalls mesenchymal progenitors in a cycling state permissive of malignant transformation and promotes OS aggressiveness in different models of different genetic backgrounds. H3K27me3 loss represents a novel mechanism of pathogenesis which sheds light on uncharted epigenetic disease mechanisms in OS.
- |||||||||| UNC1999 - University of North Carolina / Chapel Hill
IDENTIFICATION OF POTENTIAL EPIGENETIC MECHANISMS REGULATING LSECTIN EXPRESSION IN HEPATIC ANTIGEN PRESENTING CELLS (Science Lounge) - Jul 18, 2024 - Abstract #UEGW2024UEGW_294;
H3K27me3 loss represents a novel mechanism of pathogenesis which sheds light on uncharted epigenetic disease mechanisms in OS. For this purpose, immortalised KCs and LSECs lines were cultured and stimulated with selected epigenetic drugs: OTS186935 (Suv39h2 inhibitor), UNC0642 (G9a/Glp inhibitor), UNC1999 (EZH2/1 inhibitor), 5-Aza-2
- |||||||||| UNC1999 - University of North Carolina / Chapel Hill
Journal: Generation of human ILC3 from allogeneic and autologous CD34 hematopoietic progenitors toward adoptive transfer. (Pubmed Central) - Feb 5, 2024
We found that the addition of recombinant human IL-15 and the enhancer of zeste homolog 1/2 inhibitor UNC1999 promoted ILC3 generation...Finally, we observed that autologous HSPC mobilized from the blood of adults with hematological malignancies also developed into ILC3, albeit with a significantly lower capacity. Together, we developed a stroma-free protocol to generate large quantities of IL-22-producing ILC3 from healthy adult human HSPC that can be applied for adoptive transfer to prevent GvHD after allogeneic HCT.
- |||||||||| UNC1999 - University of North Carolina / Chapel Hill
Biomarker, Journal, Tumor microenvironment: Alteration of the tumor microenvironment by pharmacological inhibition of EZH2 in hepatocellular carcinoma. (Pubmed Central) - Apr 25, 2023
UNC1999, an EZH2 inhibitor, impaired growth of the murine HCC cells (H22 cells) and induced apoptosis in a dose-dependent manner...In conclusion, the study results demonstrated that EZH2 inhibitor contributed to attenuation of tumor immunity caused by TME arrangement. Combination therapy with EZH2 inhibitors and agents that reduce MDSCs might represent a novel therapeutic strategy for HCC.
- |||||||||| 5-fluorouracil / Generic mfg.
Journal: Polycomb EZH1 regulates cell cycle/5-FU sensitivity of neuroblastoma cells in concert with MYCN. (Pubmed Central) - Sep 3, 2022
Previous reports indicated neuroblastoma cells are resistant to 5-fluorouracil (5-FU) and TYMS (encoding thymidylate synthetase) has been considered the primary site of action for folate analogues. Intriguingly, UNC1999 treatment significantly sensitized MYCN-amplified neuroblastoma cells to 5-FU treatment, suggesting that EZH inhibition may be an effective strategy for development of a new epigenetic treatment for neuroblastoma.
- |||||||||| UNC1999 - University of North Carolina / Chapel Hill, TAK-243 / Takeda
Journal: A combinatorial chemical epigenetics screen identifies an off-target modulation of drug transporter function. (Pubmed Central) - May 14, 2022
These probes include TP-472, GSK-864, A-196, UNC1999, SGC-CBP30 and PFI-4, and target BRD9/7, mutant IDH1, SUV420H1/H2, EZH2/H1, p300/CBP and BRPF1B, respectively...We also provide experimental evidence of the inability of negative controls to exclude a subset of off-target effects of chemical probes. Finally, we have developed a robust cell-based assay that can quantitatively evaluate ABCG2 inhibition by drug candidates.
- |||||||||| UNC1999 - University of North Carolina / Chapel Hill
Journal: Dual Inhibition of H3K9me2 and H3K27me3 Promotes Tumor Cell Senescence without Triggering the Secretion of SASP. (Pubmed Central) - Apr 19, 2022
In this study, we used the small molecule inhibitors, UNC0642 (G9a inhibitor) and UNC1999 (EZH2 inhibitor) alone or in combination, to inhibit H3K9 and H3K27 methylation in different cancer cells...Dual inhibition of H3K9me2 and H3K27me3 suppressed the formation of cytosolic chromatin fragments, which inhibited the cGAS-STING-SASP pathway. Collectively, these data suggested that dual inhibition of H3K9 and H3K27 methylation induced senescence of highly metastatic tumor cells without triggering SASP by inhibiting the cGAS-STING-SASP pathway, providing a new mechanism for the epigenetics-based therapy targeting H3K9 and H3K27 methylation.
- |||||||||| UNC1999 - University of North Carolina / Chapel Hill
Preclinical, Journal: Development of a UPLC-MS/MS method for determination of a dual EZH1/2 inhibitor UNC1999 in rat plasma. (Pubmed Central) - Mar 23, 2022
UNC1999 was absorbed slowly and achieved a maximum concentration of 118.8 ± 12.0 ng/ml 1.5 h after oral administration. The method provides a favorable character in selectivity, linearity, accuracy, precision, recovery, matrix effects and stabilities and was suitable for describing the pharmacokinetic profile of UNC1999.
- |||||||||| UNC1999 - University of North Carolina / Chapel Hill
Journal: Enhanced Calcium Signal Induces NK Cell Degranulation but Inhibits Its Cytotoxic Activity. (Pubmed Central) - Feb 2, 2022
Further analyses revealed that the ability of conjugate formation, lytic synapse formation, and granule polarization were normal in NK cells treated with UNC1999. Cumulatively, these data indicated that induced calcium signal exclusively enhances unbalanced degranulation that further inhibits their cytotoxic activity in human NK cells.
- |||||||||| Nexavar (sorafenib) / Bayer, Amgen
Journal: EZH1/2 inhibition augments the anti-tumor effects of sorafenib in hepatocellular carcinoma. (Pubmed Central) - Jan 27, 2022
Combination treatment canceled the sorafenib-induced enhancement in H3K27me3 levels, indicating that activation of EZH2 function is one of the mechanisms of sorafenib-resistance in HCC. In conclusion, sorafenib plus EZH1/2 inhibitors may comprise a novel therapeutic approach in HCC.
- |||||||||| GSK2816126 / GSK, UNC1999 - University of North Carolina / Chapel Hill
Evaluate the role of EZH1/EZH2 in tumorigenesis of DIPG cells () - Jan 7, 2022 - Abstract #LCC2022LCC_63;
Inhibition of both EZH1/2 resulted in higher antitumor activity than only inhibiting EZH2. Collectively, our research data suggested that targeting both EZH1/2 could provide new therapeutic options for the treatment of PRC2-dependent cancers, like DIPG.
- |||||||||| UNC1999 - University of North Carolina / Chapel Hill
Journal: EZH2 targeting to improve the sensitivity of acquired radio-resistance bladder cancer cells. (Pubmed Central) - Dec 27, 2021
On the other hand, UNC1999 treatment caused the increasing of LC3B and P62 in all cells, suggested that siEZH2 and UNC1999 affect ARR cells autophagy through different mechanisms...Combined with bioinformatics data analysis, we speculate that EZH2 is an important biomolecule linking the diagnosis, radiotherapy and prognosis of BCa. EZH2 targeted therapy may be an effective way to overcome ARR of BCa, and is worthy of in-depth study.
- |||||||||| UNC1999 - University of North Carolina / Chapel Hill
[VIRTUAL] EFFECTS OF EZH2 INHIBITION ON TUMOR AND TUMOR MICROENVIRONMENT IN HEPATOCELLULAR CARCINOMA () - Oct 21, 2021 - Abstract #AASLD2021AASLD_1365;
Our results of allogenic mouse model revealed that EZH2 inhibition is associated with attenuation of tumor immunity caused by a decrease in TILs and an increase in MDSCs. These findings implicate that partnering agents which is able to reverse these alterations may be important in the treatment of HCC with EZH2 inhibitor .
- |||||||||| UNC1999 - University of North Carolina / Chapel Hill
Journal: NOTCH and EZH2 collaborate to repress PTEN expression in breast cancer. (Pubmed Central) - Aug 11, 2021
Restoration of PTEN expression can be achieved with an EZH2 inhibitor (UNC1999), a γ-secretase inhibitor (Compound E), or knockdown of EZH2 or NOTCH. These findings elucidate a mechanism of transcriptional repression of PTEN induced by NOTCH1 or NOTCH2 alterations, and identifies actionable signaling pathways responsible for driving a large subset of poor-prognosis breast cancers.
- |||||||||| azacitidine / Generic mfg.
Journal, Epigenetic controller: Contribution of DNA methylation and EZH2 in SRBC down-regulation in gastric cancer. (Pubmed Central) - Jun 23, 2021
We showed that EZH2 plays role in SRBC silencing in addition to DNA methylation. Our study, suggests that DNA methylation and EZH2 are involved in SRBC silencing and their inhibitors can be considered in cancer treatment investigations to overcome chemoresistance induced by SRBC inactivation.
- |||||||||| TAS-117 / Otsuka, UNC1999 - University of North Carolina / Chapel Hill, unesbulin (PTC596) / PTC Therap
Journal: Novel epigenetic therapies for multiple myeloma (Pubmed Central) - May 11, 2021
Finally, our mouse model with concurrent loss of the histone demethylase Utx and the activating mutation of Braf V600E in post germinal center B cells demonstrates mature B-cell malignancies including plasma cell neoplasms. Our ongoing analyses will reveal the pathogenesis of MM induced by somatic mutations, and this model is a useful tool for the development of novel molecular-targeted therapies for MM patients.
- |||||||||| GSK2816126 / GSK, UNC1999 - University of North Carolina / Chapel Hill
Journal, IO biomarker: EZH1/2 Inhibitors Favor ILC3 Development from Human HSPC-CD34 Cells. (Pubmed Central) - Jan 22, 2021
However, UNC1999 and GSK 126 favored the proliferation of no-cytotoxic CD56ILC3, according to the early expression of the AHR and ROR-γt transcription factors. Our results describe novel epigenetic mechanisms involved in the modulation of NK cell maturation that may provide new tools for designing NK cell-based immunotherapy.
- |||||||||| temozolomide / Generic mfg., UNC1999 - University of North Carolina / Chapel Hill, Tazverik (tazemetostat) / Epizyme, Eisai
Preclinical, Journal: Dissecting the role of novel EZH2 inhibitors in primary glioblastoma cell cultures: effects on proliferation, epithelial-mesenchymal transition, migration, and on the pro-inflammatory phenotype. (Pubmed Central) - Jul 29, 2020
The two novel EZH2i MC4040 and MC4041 impaired primary GBM cell viability, showing even stronger effects in combination with TMZ. They also weakened the aggressive malignant phenotype by reducing angiogenesis, EMT, cell migration/invasion and inflammation, thus they may be considered potential candidates against GBM also for combination therapies.
- |||||||||| UNC1999 - University of North Carolina / Chapel Hill
[VIRTUAL] PAUSED TRANSCRIPTION, A NOVEL MIR139 SILENCING MECHANISM DOWNSTREAM OF MLL-AF9 IN ACUTE MYELOID LEUKEMIA () - May 16, 2020 - Abstract #EHA2020EHA_378;
Inhibiting H3K27-specific methyltransferases Enhancer of Zeste-1 (EZH1) and EZH2, two critical compounds of PRC2, with UNC1999 resulted in a tremendous increase of miR-139 expression and apoptosis of MLL-AF9 AML...Furthermore, we present evidence for a POLR2M-mediated MIR139 silencing mechanism downstream of MLL-AF9 and PRC2. These results reveal new venues for novel therapies in MLL-AF9 AML.
- |||||||||| UNC1999 - University of North Carolina / Chapel Hill, Tazverik (tazemetostat) / Epizyme, Eisai
Preclinical, Journal: The Role of the Histone Methyltransferase EZH2 in Liver Inflammation and Fibrosis in STAM NASH Mice. (Pubmed Central) - May 8, 2020
In this study, we investigated that inhibition of EZH2 reduced mRNA expression of inflammatory cytokines and fibrosis markers in NASH mice. In conclusion, these results suggest that EZH2 may present a promising therapeutic target in the treatment of NASH.
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