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    DRUG CLASS:

    EED inhibitor

    Related drugs:
    4ms
    Safety and Efficacy of MAK683 in Adult Patients With Advanced Malignancies (clinicaltrials.gov)
    P1, N=139, Active, not recruiting, Novartis Pharmaceuticals | Phase classification: P1/2 --> P1
    Phase classification • Metastases
    |
    MAK683
    6ms
    Embryonic Ectoderm Development (EED) Inhibitor APG5918 Improves Chronic Kidney Disease- (CKD)-Induced Hemoglobin Insufficiency in Preclinical Models of Anemia (ASH 2023)
    76-fold of the control group, respectively, which was pharmacologically superior to effects observed with hydroxyurea at 33 µM (~6. APG-5918 also showed synergistic antianemia effects when combined with EPO. These findings support APG-5918 as a novel treatment option for CKD-induced anemia.
    Preclinical
    |
    CD34 (CD34 molecule) • HBB (Hemoglobin Subunit Beta) • SUZ12 (SUZ12 Polycomb Repressive Complex 2 Subunit)
    |
    hydroxyurea • APG-5918
    6ms
    HbF Inducing Eed Inhibitor Ftx-6058 Selectively and Reversibly Impacts Bone Marrow in Wild-Type Mice (ASH 2023)
    These findings demonstrate that inhibition of EED through FTX-6058 leads to a minimal, transient impact on the bone marrow in mice, and any transcriptional changes are rapidly reversible following cessation of dosing. A small molecule EED inhibitor has the potential to provide a new treatment for sickle cell disease without irreversibly altering the bone marrow.
    Preclinical
    |
    HBB (Hemoglobin Subunit Beta)
    9ms
    Nicardipine is a putative EED inhibitor and has high selectivity and potency against chemoresistant prostate cancer in preclinical models. (PubMed, Br J Cancer)
    Our findings provided the first preclinical evidence supporting nicardipine as a novel EED inhibitor that has the potential to be promptly tested in PCa patients to overcome chemoresistance and improve clinical outcomes.
    Preclinical • Journal
    |
    EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • BIRC5 (Baculoviral IAP repeat containing 5) • SKP2 (S-phase kinase-associated protein 2)
    |
    docetaxel
    1year
    PROTAC Linkerology Leads to an Optimized Bivalent Chemical Degrader of Polycomb Repressive Complex 2 (PRC2) Components. (PubMed, ACS Chem Biol)
    Characterization of UNC7700 and related compounds for ternary complex formation and cellular permeability to provide a rationale for the observed improvement in degradation efficiency remained challenging. Importantly, UNC7700 dramatically reduces H3K27me3 levels and is anti-proliferative in DB cells (EC = 0.79 ± 0.53 μM).
    Journal
    |
    SUZ12 (SUZ12 Polycomb Repressive Complex 2 Subunit)
    1year
    Imagawa-Matsumoto syndrome: SUZ12-related overgrowth disorder. (PubMed, Clin Genet)
    We also report on a novel IMMAS patient carrying a splicing variant (c.1023?+?1G?>?C) in SUZ12. This patient had a milder phenotype than other previously reported IMMAS cases, with no macrocephaly or overgrowth phenotypes, highlighting the clinical variation in IMMAS.
    Review • Journal
    |
    NF1 (Neurofibromin 1) • SUZ12 (SUZ12 Polycomb Repressive Complex 2 Subunit)
    |
    NF1 deletion
    1year
    Deep genomic analysis of malignant peripheral nerve sheath tumor cell lines challenges current malignant peripheral nerve sheath tumor diagnosis. (PubMed, iScience)
    Cell lines re-classified as melanomas and other sarcomas exhibited a different drug-treatment response. Deep genomic analysis, methylome-based classification, and cell-identity marker expression, challenged the identity of common MPNST cell lines, opening an opportunity to revise MPNST differential diagnosis.
    Preclinical • Journal • Tumor cell
    |
    CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • NF1 (Neurofibromin 1) • SUZ12 (SUZ12 Polycomb Repressive Complex 2 Subunit)
    over1year
    EarlyCDT Lung blood test for risk classification of solid pulmonary nodules: systematic review and economic evaluation. (PubMed, Health Technol Assess)
    Prospective cohort studies, in which EarlyCDT Lung is used among patients with identified pulmonary nodules, are required to support a future assessment of the clinical and economic value of this test. Studies should investigate the diagnostic accuracy and clinical impact of EarlyCDT Lung in combination with Brock and Herder risk assessments. A well-designed cost-effectiveness study is also required, integrating emerging relevant evidence with the recommendations in this report.
    HEOR • Review
    |
    EarlyCDT®-Lung
    over1year
    PALI1 promotes tumor growth through competitive recruitment of PRC2 to G9A-target chromatin for dual epigenetic silencing. (PubMed, Mol Cell)
    Accordingly, PALI1 and G9A drive PCa cell proliferation and invasion in vitro and xenograft tumor growth in vivo. Collectively, our study shows that PALI1 harnesses two central epigenetic mechanisms to suppress cellular differentiation and promote tumorigenesis, which can be targeted by dual EZH2 and G9A inhibition.
    Journal
    |
    JARID2 (Jumonji And AT-Rich Interaction Domain Containing 2) • SUZ12 (SUZ12 Polycomb Repressive Complex 2 Subunit)
    over1year
    Expanding the Molecular Spectrum of Gene Fusions in Endometrial Stromal Sarcoma: Novel Subunits of the Chromatin Remodeling Complexes PRC2 and NuA4/TIP60 as Alternative Fusion Partners. (PubMed, Genes Chromosomes Cancer)
    Our study expands the molecular spectrum of EPC1 and PHF1-related gene fusions in ESS to include additional novel subunits of the PRC2 and/or NuA4/TIP60 complexes. These cases displayed a monomorphic epithelioid or spindled phenotype, spanning low-grade and high-grade cytomorphology, all expressing CD10 and commonly ER and PR, and are prone to local and/or distant spread.
    Journal
    |
    PGR (Progesterone receptor) • MME (Membrane Metalloendopeptidase)
    |
    PGR expression • EZH2 positive
    over1year
    Oncogenic Roles of Polycomb Repressive Complex 2 in Bladder Cancer and Upper Tract Urothelial Carcinoma. (PubMed, Biomedicines)
    In conclusion, PRC2 and its epigenetic effects are major oncogenic mechanisms underlying both bladder cancer and UTUC. The epigenetically regulated genes of PRC2 in urothelial carcinoma were also elucidated using correlation statistics.
    Journal
    |
    FGFR1 (Fibroblast growth factor receptor 1) • ANXA5 (Annexin A5) • CNPY2 (Canopy FGF Signaling Regulator 2) • SUZ12 (SUZ12 Polycomb Repressive Complex 2 Subunit)
    over1year
    Malignant Peripheral Nerve Sheath Tumor in Children: A Clinicopathologic and Molecular Study with Parallels to the Adult Counterpart. (PubMed, Genes Chromosomes Cancer)
    Thus, H3K27me3 loss of expression may be used in the diagnosis of high grade MPNSTs in children. Moreover, a small subset of pediatric MPNST have an epithelioid morphology with different pathogenesis.
    Journal
    |
    CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • NF1 (Neurofibromin 1) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • SMARCB1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1) • SUZ12 (SUZ12 Polycomb Repressive Complex 2 Subunit)
    |
    MSK-IMPACT
    over1year
    Dual Acting Peptides Target EZH2 and AR: a New Paradigm for Effective Treatment of Castration-Resistant Prostate Cancer. (PubMed, Endocrinology)
    Despite the development of the antiandrogens enzalutamide and abiraterone for CRPC, which target the androgen receptor (AR), drug resistance usually develops within 6 months and metastatic CRPC (mCRPC) leads to lethality. These peptides are also more cytotoxic to prostate cancer cells than the combination of Enzalutamide and an EZH2 inhibitory drug, which was recently suggested to be an effective treatment of mCRPC disease. Our data show that such a dual-acting therapeutic approach can be more effective than the existing front-line drug therapies for treating deadly mCRPC.
    Journal
    |
    SUZ12 (SUZ12 Polycomb Repressive Complex 2 Subunit)
    |
    AR splice variant 7
    |
    Xtandi (enzalutamide capsule) • abiraterone acetate
    over1year
    Study of Safety, Pharmacokinetic and Efficacy of APG-5918 in Advanced Solid Tumors or Lymphomas (clinicaltrials.gov)
    P1, N=90, Recruiting, Ascentage Pharma Group Inc. | Not yet recruiting --> Recruiting
    Enrollment open • Metastases
    |
    SMARCB1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1)
    |
    EZH2 mutation
    |
    APG-5918
    over1year
    Non-canonical transcriptional regulation of INHAT subunit SET/TAF-Iβ by EZH2. (PubMed, Biochem Biophys Res Commun)
    Moreover, EZH2 and SET/TAF-Iβ levels were positively correlated, and both genes were highly expressed in various cancers including colon cancer as indicated by the analysis of TCGA database. Taken together, our study suggests the non-canonical role of EZH2 as a transcriptional activator of SET/TAF-Iβ independent of methyltransferase function in colon cancer.
    Journal
    |
    SUZ12 (SUZ12 Polycomb Repressive Complex 2 Subunit)
    over1year
    EARLY T-CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA IN CHILDHOOD (EHOC 2022)
    Patients with ETP-ALL had high risk of hematological relapse treated at St Jude Children's Research Hospital (3). For relapsed and refractory patients, the use of acute myeloid leukemia-oriented therapies such as FLAG-IDA regimen or targeted agents may be of benefit for some patients, including FLT3 inhibitors, tyrosine kinase inhibitors, BCL-2 inhibitors such as venetoclax, or JAK/STAT inhibitors in patients with JAK mutations or fusions (1,2,4,5,7).
    Clinical • IO biomarker
    |
    KRAS (KRAS proto-oncogene GTPase) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • DNMT3A (DNA methyltransferase 1) • NOTCH1 (Notch 1) • NF1 (Neurofibromin 1) • CD8 (cluster of differentiation 8) • RUNX1 (RUNX Family Transcription Factor 1) • ETV6 (ETS Variant Transcription Factor 6) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • WT1 (WT1 Transcription Factor) • JAK1 (Janus Kinase 1) • SETD2 (SET Domain Containing 2, Histone Lysine Methyltransferase) • CD33 (CD33 Molecule) • CD34 (CD34 molecule) • IL7R (Interleukin 7 Receptor) • JAK3 (Janus Kinase 3) • CD5 (CD5 Molecule) • ITGAM (Integrin, alpha M) • PHF6 (PHD Finger Protein 6) • SH2B3 (SH2B Adaptor Protein 3) • BCL11B (BAF Chromatin Remodeling Complex Subunit BCL11B) • GATA3 (GATA binding protein 3) • ANPEP (Alanyl Aminopeptidase, Membrane) • SUZ12 (SUZ12 Polycomb Repressive Complex 2 Subunit)
    |
    KRAS mutation • CDKN2A mutation • CD8 expression • JAK3 mutation
    |
    Venclexta (venetoclax)
    over1year
    Polycomb Directed Cell Fate Decisions in Development and Cancer. (PubMed, Epigenomes)
    We will specifically describe how PRC2 dysregulation in different cell types can promote phenotypic plasticity and/or non-mutational epigenetic reprogramming, inducing the development of highly aggressive epithelial neuroendocrine carcinomas, including prostate, small cell lung, and Merkel cell cancer. With this, EZH2 has emerged as an important actionable therapeutic target in such cancers.
    Review • Journal
    |
    SUZ12 (SUZ12 Polycomb Repressive Complex 2 Subunit)
    over1year
    Tumor-intrinsic PRC2 inactivation drives a context-dependent immune-desert microenvironment and is sensitized by immunogenic viruses. (PubMed, J Clin Invest)
    Our results identify molecular mechanisms of PRC2 inactivation-mediated, context-dependent epigenetic reprogramming that underline the immune-desert phenotype in cancer. Our studies also point to intratumoral delivery of immunogenic viruses as an initial therapeutic strategy to modulate the immune-desert TME and capitalize on the clinical benefit of ICB.
    Journal
    |
    IFNG (Interferon, gamma) • SUZ12 (SUZ12 Polycomb Repressive Complex 2 Subunit)
    over1year
    Human acute leukemia utilizes branched-chain amino acid catabolism to maintain stemness through regulating PRC2 function. (PubMed, Blood Adv)
    Inhibition of BCAA catabolism in primary AML or ALL cells specifically inactivates polycomb repressive complex 2 (PRC2) function, an epigenetic regulator for stem cell signatures, through inhibiting transcription of PRC components, such as zeste homolog 2 (EZH2) and embryonic ectoderm development (EED). Accordingly, BCAA catabolism plays an important role in maintenance of stemness in primary human AML and ALL, and molecules related to the BCAA metabolism pathway should be critical targets for acute leukemia treatment.
    Journal
    |
    CD34 (CD34 molecule) • BCAT1 (Branched Chain Amino Acid Transaminase 1 )
    over1year
    Epigenetic silencing of E-cadherin gene induced by lncRNA MALAT-1 in acute myeloid leukaemia. (PubMed, J Clin Lab Anal)
    Our findings verified that MALAT-1 might lead to the transcriptional silencing of E-cadherin gene through the trimethylation of H3K27 mediated by recruiting EZH2 and SUZ12.
    Journal
    |
    DNMT3A (DNA methyltransferase 1) • EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • CDH1 (Cadherin 1) • MALAT1 (Metastasis associated lung adenocarcinoma transcript 1) • DNMT1 (DNA methyltransferase 1) • DNMT3B (DNA Methyltransferase 3 Beta) • SUZ12 (SUZ12 Polycomb Repressive Complex 2 Subunit)
    |
    CDH1 expression
    over1year
    PRC2 Heterogeneity Drives Tumor Growth in Medulloblastoma. (PubMed, Cancer Res)
    Assessing clones of a human medulloblastoma cell line with different EED levels confirmed that EEDlow cells can stimulate the growth of EEDhigh cells through paracrine IGF2 signaling. Thus, PRC2 heterogeneity plays an oncogenic role in medulloblastoma through both intrinsic growth competence and non-cell autonomous mechanisms in distinct tumor subclones.
    Journal
    |
    IGF2 (Insulin-like growth factor 2)
    almost2years
    Erythema elevatum diutinum in a patient with Crohn's disease: a very rare variant of chronic cutaneous vasculitis (ECP 2022)
    The histopathologic features of EED vary according to the age of the lesions, with development of variable fibrosis and fasciculated spindle cell proliferation in late stages. The diferential diagnosis is made with an infammatory pseudotumour, dermatofbrosarcoma protuberans, sclerotic neurofbroma, sclerosing perineuroma, tendon sheath fibroma, and hyalinized leiomyoma. The aetiology of EED is unknown; it has been proposed to be an immunocomplex-mediated disease, with viral or bacterial antigens being involved, which would explain the association between EED and CD.
    Clinical
    |
    CD34 (CD34 molecule)
    almost2years
    The PRC2 molecule EED is a target of epigenetic therapy for neuroblastoma. (PubMed, Eur J Cell Biol)
    This combined epigenetic treatment up-regulated cell cycle-regulated and differentiation-related genes. The ChIP sequencing analysis of histone codes and PRC molecules suggested an epigenetic background for the de-repression of down-regulated genes in MYCN-amplified/PRC2 up-regulated NB.
    Journal
    |
    MYCN (MYCN Proto-Oncogene BHLH Transcription Factor)
    |
    MYCN amplification
    |
    Zolinza (vorinostat)
    almost2years
    Study of Safety, Pharmacokinetic and Efficacy of APG-5918 in Advanced Solid Tumors or Lymphomas (clinicaltrials.gov)
    P1, N=90, Not yet recruiting, Ascentage Pharma Group Inc. | Trial completion date: Oct 2024 --> Sep 2025
    Trial completion date
    |
    SMARCB1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1) • CAST (Calpastatin)
    |
    EZH2 mutation
    |
    APG-5918
    almost2years
    Loss of dimethylated H3K27 (H3K27me2) expression is not a specific marker of malignant peripheral nerve sheath tumor (MPNST): An immunohistochemical study of 137 cases, with emphasis on MPNST and melanocytic tumors. (PubMed, Ann Diagn Pathol)
    We conclude that H3K27me2 loss is not specific for MPNST, and like H3K27me3, should be used in the appropriate clinicopathologic, immunohistochemical and molecular genetic context. Loss of H3K27me2 with retained H3K27me3 is a common feature of "blue nevus family" melanocytic tumors known to harbor GNAQ/GNA11 mutations.
    Journal
    |
    NF1 (Neurofibromin 1) • GNAQ (G Protein Subunit Alpha Q) • GNA11 (G Protein Subunit Alpha 11) • SUZ12 (SUZ12 Polycomb Repressive Complex 2 Subunit)
    |
    GNAQ mutation • GNA11 mutation
    almost2years
    Polycomb repressive complex 2 mutations predict survival benefit in advanced cancer patients treated with immune checkpoint inhibitors. (PubMed, Immunooncol Technol)
    Inactivating mutations in the PRC2 chromatin silencing machinery, although rare, may predict favorable outcomes in ICI-treated patients with metastatic cancers. This warrants prospective confirmation, and suggests that epigenetic regulators could serve as surrogate markers to guide ICI treatment decisions.
    Journal • Checkpoint inhibition • PD(L)-1 Biomarker • IO biomarker
    |
    EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • SUZ12 (SUZ12 Polycomb Repressive Complex 2 Subunit)
    |
    EZH2 mutation • PRC2 mutation
    almost2years
    Study of Safety, Pharmacokinetic and Efficacy of APG-5918 in Advanced Solid Tumors or Lymphomas (clinicaltrials.gov)
    P1, N=84, Not yet recruiting, Ascentage Pharma Group Inc.
    New P1 trial
    |
    SMARCB1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1)
    |
    EZH2 mutation
    |
    APG-5918
    2years
    Induction of senescence-associated secretory phenotype underlies the therapeutic efficacy of PRC2 inhibition in cancer. (PubMed, Cell Death Dis)
    The genes potential regulated by PRC2 in neuroblastoma samples exhibited significant enrichment of ECM and senescence associated inflammation, supporting the clinical relevance of our results. Altogether, our results unravel the pharmacological mechanism of PRC2 inhibitors and propose a combination strategy for MAK683 and other PRC2 drugs.
    Journal
    |
    CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • ARID1A (AT-rich interaction domain 1A) • SMARCB1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1) • MMP2 (Matrix metallopeptidase 2) • GBP1 (Guanylate Binding Protein 1) • SUZ12 (SUZ12 Polycomb Repressive Complex 2 Subunit)
    |
    EZH2 mutation
    |
    MAK683
    2years
    Sequential stabilization of RNF220 by RLIM and ZC4H2 during cerebellum development and Shh-group medulloblastoma progression. (PubMed, J Mol Cell Biol)
    Disease-causative human RLIM and ZC4H2 mutations affect their interaction and regulation. Therefore, our study sheds light on the regulation of Shh signaling during cerebellar development and MB progression and provides insights into neural disorders caused by RLIM or ZC4H2 mutations.
    Journal
    |
    GLI1 (GLI Family Zinc Finger 1)
    2years
    Tumor-intrinsic PRC2 inactivation drives a context-dependent immune-desert tumor microenvironment (AACR 2022)
    Importantly, our findings highlight genetic-inactivation of PRC2 as a novel context-dependent ICB therapeutic resistance biomarker in cancer, and caution that therapeutic strategies that non-selectively target PRC2 in the host may lead to undesirable context-dependent immune evasion and ICB resistance in tumors. Our studies also point to intratumoral delivery of immunogenic therapeutic viruses as an initial strategy to modulate the immune-desert TME and capitalize on the clinical benefit of ICB.
    IFNG (Interferon, gamma) • SUZ12 (SUZ12 Polycomb Repressive Complex 2 Subunit)
    2years
    Preclinical development of embryonic ectoderm development (EED) inhibitor APG-5918/EEDi-5273 for cancer therapy (AACR 2022)
    With regulatory approval of EZH2 inhibitor tazemetostat, a potentially effective successful cancer therapeutic strategy is now available for patients with epitheloid sarcoma and relapsed or refractory follicular lymphoma. In a mouse xenograft model derived from EZH2mut KARPAS-422 DLBCL cells, single-agent APG-5918 conferred potent and dose-dependent antitumor activity, resulting in durable complete tumor regression that correlated with inhibition of H3K27me3, induction of PRC2 target genes, and drug exposure in tumors. In summary, our results provide scientific rationale for the clinical development of APG-5918/EEDi-5273 in EZH2mut lymphomas and, potentially, other hematologic malignancies and solid tumors.
    Preclinical
    |
    EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • SUZ12 (SUZ12 Polycomb Repressive Complex 2 Subunit)
    |
    EZH2 mutation
    |
    Tazverik (tazemetostat) • APG-5918
    over2years
    Diverse, Potent, and Efficacious Inhibitors That Target the EED Subunit of the Polycomb Repressive Complex 2 Methyltransferase. (PubMed, J Med Chem)
    In this paper we disclose the discovery of potent and orally bioavailable EED ligands with good solubilities. The solubility of the EED ligands was optimized through a variety of design tactics, with the resulting compounds exhibiting in vivo efficacy in EZH2-driven tumors.
    Journal
    |
    EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit)
    over2years
    Multi-omics analysis identifies therapeutic vulnerabilities in triple-negative breast cancer subtypes. (PubMed, Nat Commun)
    Pharmacological inhibition of PRC2 subunits EZH2 or EED restores MHC-I expression and enhances chemotherapy efficacy in murine tumor models, providing a rationale for using PRC2 inhibitors in PD-L1 negative mesenchymal tumors. Subtype-specific differences in immune cell composition and differential genetic/pharmacological vulnerabilities suggest additional treatment strategies for TNBC.
    Journal • Tumor Mutational Burden • PD(L)-1 Biomarker • IO biomarker
    |
    TMB (Tumor Mutational Burden) • AR (Androgen receptor)
    |
    PD-L1 expression • PD-L1 negative