UNC1999 / University of North Carolina-Chapel Hill - LARVOL DELTA

Dysregulation of histone methylation in SV40 chromosomes during replication results in aberrant transcription and chromatin structure. (PubMed, Tumour Virus Res) - "The inhibitors used included GSK-LSD1 to inhibit demethylation of H3K4me1 and H3K9me1, A366 to inhibit the introduction of H3K9me1, and UNC1999 to inhibit the introduction of H3K27me3. The results are consistent with a regulatory model in which nucleosomes carrying H3K9me1 and H3K27me3 located at the ends of the SV40 regulatory region act to regulate transcription."

Journal

Epigenetic regulation of LSECtin in hepatic antigen presenting cells during experimental cirrhosis (EASL 2025) - "Immortalized KCs and LSECs were treated with epigenetic effector inhibitory drugs (OTS186935-Suv39h2i, UNC0642-G9a/Glpi, UNC1999-EZH2/1i, 5-Aza-2'-deoxycitidine-DNMTi), alone and in combination with IL-4, an LSECtin expression inductor... The increment of LSECtin expression by passive demethylation of DNA and methylation array results point out methylation of Clec4g promoter is a key mechanism in expression regulation. Modulation of LSECtin expression both in vitro and in vivo by epigenetic effector inhibitory drugs strongly suggest that HPTMs profile alteration contributes to protein regulation during CLD, thus positioning periodical administration of epigenetic inhibitors as a candidate for LSECtin expression recovery in the pathological scenario."

Fibrosis • Hepatology • Immunology • CD4 • CD8 • CLEC4G • IL17A • IL4

H3K27-me3 Inhibition Induces YTHDF2-Mediated Decay of m6A-Marked Severe Acute Respiratory Syndrome Coronavirus 2 Transcripts. (PubMed, J Med Virol) - "The application of the H3K27-demethyltransferase or KDM6A/B inhibitor GSK-J4 can restore H3K27-me3 levels and mitigating the decay of viral mRNA in UNC1999-treated SARS-CoV-2-infected cells. Furthermore, long-term sequential passage (P = 50) of the virus in the presence of UNC1999 did not yield any UNC1999-resistant SARS-CoV-2 mutants. In conclusion, by integrating transcriptomics, molecular virology and functional analyses, we for the first time demonstrated that inhibition of H3K27-me3 induces m6A-mediated decay of SARS-CoV-2 transcripts, highlighting UNC1999 as novel antiviral candidate against SARS-CoV-2."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • KDM6A • YTHDF2

Polycomb repressive complex 2 (PRC2) pathway's role in cancer cell plasticity and drug resistance. (PubMed, Funct Integr Genomics) - "Inhibitors like MAK683 and EED226 disrupt EED's ability to maintain PRC2 activity, thereby reducing H3K27me3 levels and reactivating tumor suppressor genes. Valemetostat, a dual inhibitor of both EZH2 and EED, has shown promising results in aggressive cancers like diffuse large B-cell lymphoma and small-cell lung cancer, underlining the therapeutic potential of targeting multiple PRC2 components...Tazemetostat, a selective EZH2 inhibitor, has demonstrated significant clinical efficacy in EZH2-mutant cancers, such as non-Hodgkin lymphomas and epithelioid sarcoma. However, the compensatory function of enhancer of zeste homolog 1 (EZH1) in some cancers requires dual inhibition strategies, as seen with agents like UNC1999 and Tulmimetostat, which target both EZH1 and EZH2. Given PRC2's multifaceted role in cancer biology, its inhibition represents a promising avenue for therapeutic intervention. The continued development of PRC2 inhibitors and exploration of their..."

IO biomarker • Journal • Review • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Genito-urinary Cancer • Hematological Malignancies • Lung Cancer • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Prostate Cancer • Sarcoma • Small Cell Lung Cancer • Soft Tissue Sarcoma • Solid Tumor • EZH2

AKR1B1 is Required for Maintaining Acute Leukemia Cell Survival by Epigenetic Silencing of Tumor Suppressor Genes. (PubMed, Biochem Genet) - "EZH2 inhibitor UNC1999 combined with knockdown of AKR1B1 showed synergistic inhibitory effect on acute leukemia cells. AKR1B1 is essential for the leukemogenesis and may serve as a potential therapeutic target to treat acute leukemia patients."

Journal • Hematological Malignancies • Leukemia • Oncology • Transplantation • AKR1B1

Ezh2 Delays Activation of Differentiation Genes During Normal Cerebellar Granule Neuron Development and in Medulloblastoma. (PubMed, bioRxiv) - "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."

Journal • Brain Cancer • Medulloblastoma • Oncology • Solid Tumor

NOVEL EPIGENETIC MECHANISMS DRIVE AGGRESSIVE OSTEOSARCOMA PATHOGENESIS AND DRUG RESISTANCE (CTOS 2024) - "Although aggressive, EZHIP expressing cells demonstrated enhanced sensitivity to EZH1/2 inhibitors UNC1999, the FDA-approved drug Tazemetostat and EZH2 Proteolysis Chimeras (PROTACs). EZHIP is a novel oncogene in a substantial subset of high-grade OS tumors. EZHIP is a novel oncogene in a substantial subset of high-grade OS tumors. 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."

Oncology • Osteosarcoma • Sarcoma • Solid Tumor • EZH2

IDENTIFICATION OF POTENTIAL EPIGENETIC MECHANISMS REGULATING LSECTIN EXPRESSION IN HEPATIC ANTIGEN PRESENTING CELLS (UEGW 2024) - "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’-deoxycitidine (DNMT inhibitor) with or without IL-4, an LSECtin inductor... LSECtin expression upregulation by DNA passive demethylation together with methylation array analysis strongly points out DNA methylation as a regulatory mechanism of LSECtin expression. On the other hand, LSECtin expression modulation by epigenetic drugs, altogether with the absence of a specific peak profile at Clec4g suggests a more complex, indirect effect of HPTMs in the protein regulation."

Hepatology • CLEC4G • IL4

Chitosan/dextran-based organohydrogel delivers EZH2 inhibitor to epigenetically reprogram chemo/immuno-resistance in unresectable metastatic melanoma. (PubMed, Carbohydr Polym) - "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."

Journal • Metastases • Melanoma • Oncology • Solid Tumor • PVR • TIGIT

Dual inhibition of enhancer of zeste homolog 1 2 induces pyroptosis, modulates oncogenic signaling pathways & sensitizes hepatocellular carcinoma to valemetostat & docetaxel treatments (AACR 2024) - "HCC is a global health concern, with chemotherapy resistance and patient recurrence posing significant challenges to liver cancer treatment. The antitumor effects and pyroptosis were enhanced by using a dual inhibitor, UNC1999, for EZH1/2, resulting in a marked increase in the sensitivity of tested cells to the Val/Doc treatment invitro. The present study unequivocally demonstrated that dual inhibition of EZH1/2 acts as a potent sensitizer of HCC cells to Val/Doc treatment, which might be a promising therapeutic approach for inducing cellular pyroptosis in HCC cell lines."

IO biomarker • Gastrointestinal Cancer • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • BAX • BCL2 • BCL2L1 • CASP3 • CTNNB1 • EZH2 • STAT3

Generation of human ILC3 from allogeneic and autologous CD34 hematopoietic progenitors toward adoptive transfer. (PubMed, Cytotherapy) - "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."

Journal • Acute Graft versus Host Disease • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Oncology • Transplantation • CD34 • IL22

EZH2 and matrix co-regulate phenotype and KCNB2 expression in bladder smooth muscle cells. (PubMed, Am J Clin Exp Urol) - "Regulation of KCNB2 at the promoter demonstrated dynamic changes in H3K27me3 during COBD and obstruction. In vitro models suggest that matrix plays a role in regulation of EZH2, H3K27me3 and KCNB2, which may play a role in the regulation of smooth muscle phenotype in vivo."

Journal

Alteration of the tumor microenvironment by pharmacological inhibition of EZH2 in hepatocellular carcinoma. (PubMed, Int Immunopharmacol) - "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."

Biomarker • Journal • Tumor microenvironment • Gastrointestinal Cancer • Genetic Disorders • Hepatocellular Cancer • Immune Modulation • Immunology • Obesity • Oncology • Primary Immunodeficiency • Solid Tumor • CCL8 • CD8 • IFNG

EZH2-mediated H3K27me3 is a predictive biomarker and therapeutic target in uveal melanoma. (PubMed, Front Genet) - "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."

Biomarker • Journal • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • EZH2

Combinatorial Anticancer Drug Screen Identifies Off-Target Effects of Epigenetic Chemical Probes. (PubMed, ACS Chem Biol) - "These probes are TP-472, GSK864, A-196, UNC1999, SGC-CBP30, and PFI-4 (and its related analogues GSK6853 and GSK5959), and they target BRD9/7, mutant IDH1, SUV420H1/2, EZH2/1, p300/CBP, and BRPF1B, respectively. We also provide experimental evidence that several negative control compounds cannot exclude a subset of off-target effects of chemical probes. Finally, potentiation of TAK-243 cytotoxicity can serve as a quantitative measure of ABCG2-inhibitory activity."

Journal • Hematological Disorders • Hematological Malignancies • Oncology • Targeted Protein Degradation • ABCG2 • IDH1

Polycomb EZH1 regulates cell cycle/5-FU sensitivity of neuroblastoma cells in concert with MYCN. (PubMed, Cancer Sci) - "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."

Journal • Gene Therapies • Neuroblastoma • Oncology • Solid Tumor • CCNA1 • EZH2 • MYCN • TYMS

A combinatorial chemical epigenetics screen identifies an off-target modulation of drug transporter function. (PubMed, FASEB J) - "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."

Journal • Hematological Disorders • Hematological Malignancies • Lung Adenocarcinoma • Lung Cancer • Multiple Myeloma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • ABCG2 • IDH1

Dual Inhibition of H3K9me2 and H3K27me3 Promotes Tumor Cell Senescence without Triggering the Secretion of SASP. (PubMed, Int J Mol Sci) - "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."

Journal • Oncology • STING

Palmitate-Triggered COX2/PGE2-Related Hyperinflammation in Dual-Stressed PdL Fibroblasts Is Mediated by Repressive H3K27 Trimethylation. (PubMed, Cells) - "UNC1999-induced H3K27me3 inhibition reversed the hyperinflammatory responses of dual-stressed PA cultures characterized by increased COX2 expression, PGE2 secretion and THP1 adhesion. The reduced expression of the gene encoding the anti-inflammatory cytokine IL-10 and the increased presence of H3K27me3 at its promoter-associated sites were reversed by inhibitor treatment. Thus, the data highlight an important epigenetic interplay between the different stimuli to which the PdL is exposed."

Journal • Dental Disorders • Dyslipidemia • Genetic Disorders • Immunology • Inflammation • Obesity • Periodontitis • GLI2 • IL10

SOX8 Affects Tumoral SPARC Expression by Regulating EZH2 to Attenuate Effectiveness of albumin-bound paclitaxel in PDAC. (PubMed, Int J Biol Sci) - "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."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • EZH2 • SOX2 • SPARC

Evaluate the role of EZH1/EZH2 in tumorigenesis of DIPG cells (LCC 2022) - "First, we investigated the effects of GSK126 (a highly selective EZH2 inhibitor) and UNC1999 (a dual EZH1 and EZH2 inhibitor) that both are an S-Adenosyl methionine (SAM) competitive inhibitor of EZH1/EZH2 on cell viability in DIPG cell lines. 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."

Brain Cancer • Diffuse Intrinsic Pontine Glioma • Glioma • Oncology • Pediatrics • Solid Tumor • EZH2 • RBBP4

MicroRNA-20a Suppresses Tumor Proliferation and Metastasis in Hepatocellular Carcinoma by Directly Targeting EZH1. (PubMed, Front Oncol) - "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."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • EZH2 • MIR20A

EZH2 targeting to improve the sensitivity of acquired radio-resistance bladder cancer cells. (PubMed, Transl Oncol) - "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."

Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • EZH2

Enhanced Calcium Signal Induces NK Cell Degranulation but Inhibits Its Cytotoxic Activity. (PubMed, J Immunol) - "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."

Journal

Development of a UPLC-MS/MS method for determination of a dual EZH1/2 inhibitor UNC1999 in rat plasma. (PubMed, Bioanalysis) - "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."

Journal • Preclinical • EZH2