UNC1999

In this study, we found histone 3 lysine 27 (H3K27) demethylated by an inhibitor of histone methyltransferase EZH2 could epigenetically reverse the resistance to chemo-drug paclitaxel (PTX), or enhance the efficacy of immune checkpoint inhibitor anti-TIGIT via downregulating TIGIT ligand CD155. As results, local injection of OHG loaded with EZH2 inhibitor UNC1999, PTX and anti-TIGIT did not only synergistically enhance the cytotoxicity of PTX, but also reprogrammed the immune resistance via bi-directionally blocking TIGIT/CD155 axis, leading to the recruitment of cytotoxic effector cells into tumor and conferring a systemic immune memory to prevent lung metastasis. Hence, this polysaccharides-based OHG represents a potential in-situ epigenetic-, chemo- and immunotherapy platform to treat unresectable metastatic melanoma.

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, 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.

UNC 1999, an EZH2 inhibitor, can downregulate H3K27me3 expression and has the most potency to inhibit OMM1 cell growth by the cell cycle and ferroptosis pathway. These results indicate that H3K27me3 can be a biomarker predicting a poor prognosis of UM. EZH2 is the potential therapeutic target for UM.

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.

We identified 6 epigenetic probes that significantly potentiated the cytotoxicity of TAK-243, a first-in-class ubiquitin-activating enzyme (UBA1) inhibitor evaluated in several solid and hematologic malignancies. 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.

EZH2 inhibitor, UNC1999, can reverse the effect of SOX8 on chemo-resistance of albumin-bound paclitaxel. Collectively, our data revealed SOX8/EZH2/SPARC signaling induced primary chemo-resistance of albumin-bound paclitaxel in pancreatic ductal adenocarcinoma.

Both the lentiviral knockdown and the pharmacological inhibition of EZH1/2 (UNC1999) diminished the level of H3K27me3 and suppressed cell growth in liver cancer cells, compared with EZH1 or EZH2 single knockdown. 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.

We demonstrated that miR-20a suppresses the tumor proliferation and metastasis in HCC by directly targeting EZH1. UNC1999 can inhibit tumor proliferation in vivo and increase the sensitivity of hepatoma cell lines to sorafenib.

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.

H22 cells, a BALB/c background HCC cell line, were treated with EZH2 inhibitor UNC1999 in culture... 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 .

Moreover, UNC1999 and a selective Akt inhibitor TAS-117 synergistically inhibit the growth of MM cells through epigenetic mechanisms...Interestingly, a microtubule polymerization inhibitor PTC596 cooperatively downregulates BMI1 protein with proteasome inhibitors, exhibiting in-vitro and in-vivo cytotoxicity in MM cells. 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.

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.

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.

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.

Also, we surveyed SRBC expression after 5-azacitidine and UNC1999 treatments of AGS cell line. 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.

To identify potential therapeutics for NASH, we tested small-molecule inhibitors of the epigenetic target histone methyltransferase EZH2, Tazemetostat (EPZ-6438), and UNC1999 in STAM NASH mice. 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.