epz-6438 and Neoplasms

Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that can change the expression of downstream target genes by catalyzing the trimethylation of lysine 27 of histone H3 (H3K27me3). Studies have found that EZH2 is highly expressed in a variety of tumor tissues and is closely related to the occurrence, development, invasion, and metastasis of tumors; therefore, EZH2 is becoming a new molecular target in antitumor therapy. Tazemetostat (EPZ-6438) was approved in 2020 as the first inhibitor targeting catalytic EZH2 for the treatment of epithelioid sarcoma. In addition, a variety of EZH2 inhibitors are being investigated in basic and clinical research for the treatment of tumors, and encouraging results have been obtained. This article systematically reviews the research progress on EZH2 inhibitors and proteolysis targeting chimera (PROTAC)-based EZH2 degradation agents with a focus on their design strategies, structure-activity relationships (SARs), and safety and clinical manifestations.

Topics: Animals; Enhancer of Zeste Homolog 2 Protein; Enzyme Inhibitors; Hematologic Neoplasms; Histone Methyltransferases; Humans; Molecular Targeted Therapy; Neoplasms; Structure-Activity Relationship

EZH2, the catalytic subunit of PRC2, catalyzes histone H3 lysine 27 (H3K27) trimethylation to induce the agglutination of chromosomes and in turn represses the transcription of the target genes. Numerous reports indicate that EZH2 is overexpressed in a variety of malignant tumor tissues. Therefore, targeting EZH2 protein is a promising strategy for cancer treatment. So far, many small molecule EZH2 specific inhibitors have entered clinical trials, but many of them harbored limited clinical efficacy. New technologies and methods are imperative to enhance the anticancer activity of EZH2. In this review, the structure and biological functions of EZH2 protein will be reviewed. The internal relationship between EZH2 and various diseases will be expounded. The development status of specific inhibitors for EZH2, and the latest progress of new strategies such as drug combination, dual-target inhibitors, targeted protein degradation technology and protein-protein interactions (PPI) inhibitors will be emphatically summarized and analyzed.

Topics: Catalytic Domain; Enhancer of Zeste Homolog 2 Protein; Enzyme Inhibitors; Humans; Neoplasms

PRC2 is a histone methyltransferase complex associated with several cancer types. Tazemetostat was recently approved as the first inhibitor targeting the catalytic subunit EZH2 and several other EZH2 inhibitors are now under clinical evaluation. Beyond EZH2, researchers have also explored other approaches including PRC2 activators, dual agents inhibiting both EZH1 and EZH2, allosteric inhibitors binding to EED, and compounds which induce the degradation of PRC2 constituent proteins.. This review provides an overview of anticancer therapies targeting PRC2 during the period 2016-2020 including clinical trials, patents and the scientific literature.. The approval of tazemetostat marks the clinical validation of EZH2 for the treatment of cancer. Despite this success many questions remain; for instance, tazemetostat was briefly placed on clinical hold for safety concerns, while another EZH2 inhibitor (GSK126) demonstrated insufficient efficacy during a Phase I/II trial. It is important to understand these risks as PRC2 therapies progress through clinic evaluation. Alternative approaches to target PRC2 may offer distinct advantages over the inhibition of EZH2, including the potential to overcome EZH2 resistance mutations. However, these emerging modalities may also incur new challenges as they progress toward the clinic. Nonetheless, the diversity of agents under development represents a wealth of therapeutic options for future patients.

Topics: Animals; Antineoplastic Agents; Benzamides; Biphenyl Compounds; Drug Resistance, Neoplasm; Enhancer of Zeste Homolog 2 Protein; Humans; Indoles; Molecular Targeted Therapy; Morpholines; Mutation; Neoplasms; Patents as Topic; Polycomb Repressive Complex 2; Pyridones

The polycomb repressive complex 2 (PRC2) is composed of three core subunits, enhancer of zeste 2 (EZH2), embryonic ectoderm development (EED), and suppressor of zeste 12 (SUZ12), along with a number of accessory proteins. It is the key enzymatic protein complex that catalyzes histone H3 lysine 27 (H3K27) methylation to mediate epigenetic silencing of target genes. PRC2 thus plays essential roles in maintaining embryonic stem cell identity and in controlling cellular differentiation. Studies in the past decade have reported frequent overexpression or mutation of PRC2 in various cancers including prostate cancer and lymphoma. Aberrant PRC2 function has been extensively studied and proven to contribute to a large number of abnormal cellular processes, including those that lead to uncontrolled proliferation and tumorigenesis. Significant efforts have recently been made to develop small molecules targeting PRC2 function for potential use as anticancer therapeutics. In this review, we describe recent approaches to identify and develop small molecules that target PRC2. These various strategies include the inhibition of the function of individual PRC2 core proteins, the disruption of PRC2 complex formation, and the degradation of its subunits.

Topics: Animals; Antineoplastic Agents; Enhancer of Zeste Homolog 2 Protein; Histones; Humans; Indoles; Neoplasms; Polycomb Repressive Complex 2; Small Molecule Libraries; Structure-Activity Relationship

Enhancer of zeste homolog 2 (EZH2) is enzymatic catalytic subunit of polycomb repressive complex 2 (PRC2) that can alter downstream target genes expression by trimethylation of Lys-27 in histone 3 (H3K27me3). EZH2 could also regulate gene expression in ways besides H3K27me3. Functions of EZH2 in cells proliferation, apoptosis, and senescence have been identified. Its important roles in the pathophysiology of cancer are now widely concerned. Therefore, targeting EZH2 for cancer therapy is a hot research topic now and different types of EZH2 inhibitors have been developed. In this review, we summarize the structure and action modes of EZH2, focusing on up-to-date findings regarding the role of EZH2 in cancer initiation, progression, metastasis, metabolism, drug resistance, and immunity regulation. Furtherly, we highlight the advance of targeting EZH2 therapies in experiments and clinical studies.

Topics: Adenosine; Antineoplastic Agents; Benzamides; Biphenyl Compounds; Cell Cycle; Cell Transformation, Neoplastic; Clinical Trials as Topic; Combined Modality Therapy; Drug Resistance, Neoplasm; Enhancer of Zeste Homolog 2 Protein; Epigenetic Repression; Histone Code; Histones; Humans; Methylation; Morpholines; Multicenter Studies as Topic; Neoplasm Metastasis; Neoplasm Proteins; Neoplasms; Polycomb Repressive Complex 2; Pyridones; Structure-Activity Relationship; Transcriptional Activation; Tumor Microenvironment

Recent genomic studies have resulted in an emerging understanding of the role of chromatin regulators in the development of cancer. EZH2, a histone methyl transferase subunit of a Polycomb repressor complex, is recurrently mutated in several forms of cancer and is highly expressed in numerous others. Notably, both gain-of-function and loss-of-function mutations occur in cancers but are associated with distinct cancer types. Here we review the spectrum of EZH2-associated mutations, discuss the mechanisms underlying EZH2 function, and synthesize a unifying perspective that the promotion of cancer arises from disruption of the role of EZH2 as a master regulator of transcription. We further discuss EZH2 inhibitors that are now showing early signs of promise in clinical trials and also additional strategies to combat roles of EZH2 in cancer.

Topics: Benzamides; Biphenyl Compounds; Drug Resistance, Neoplasm; Enhancer of Zeste Homolog 2 Protein; Humans; Indazoles; Indoles; Molecular Targeted Therapy; Morpholines; Mutation; Neoplasms; Polycomb Repressive Complex 2; Polycomb-Group Proteins; Pyridones

Childhood cancer represents more than 100 rare and ultra-rare diseases, with an estimated 12,400 new cases diagnosed each year in the United States. As such, this much smaller patient population has led to pediatric oncology drug development lagging behind that for adult cancers. Developing drugs for pediatric malignancies also brings with it a number of unique trial design considerations, including flexible enrollment approaches, age-appropriate formulation, acceptable sampling schedules, and balancing the need for age-stratified dosing regimens, given the smaller patient populations. The regulatory landscape for pediatric pharmacotherapy has evolved with U.S. Food and Drug Administration (FDA) legislation such as the 2012 FDA Safety and Innovation Act. In parallel, regulatory authorities have recommended the application of physiologically based pharmacokinetic (PBPK) modeling, for example, in the recently issued FDA Strategic Plan for Accelerating the Development of Therapies for Pediatric Rare Diseases. PBPK modeling provides a quantitative and systems-based framework that allows the effects of intrinsic and extrinsic factors on drug exposure to be modeled in a mechanistic fashion. The application of PBPK modeling in drug development for pediatric cancers is relatively nascent, with several retrospective analyses of cytotoxic therapies, and latterly for targeted agents such as obatoclax and imatinib. More recently, we have employed PBPK modeling in a prospective manner to inform the first pediatric trials of pinometostat and tazemetostat in genetically defined populations (mixed lineage leukemia-rearranged and integrase interactor-1-deficient sarcomas, respectively). In this review, we evaluate the application of PBPK modeling in pediatric cancer drug development and discuss the important challenges that lie ahead in this field.

Topics: Adolescent; Age of Onset; Antineoplastic Agents; Benzamides; Benzimidazoles; Biphenyl Compounds; Child; Child, Preschool; Drug Approval; Drug Discovery; Humans; Infant; Infant, Newborn; Medical Oncology; Models, Biological; Morpholines; Neoplasms; Pediatrics; Pharmacogenetics; Pyridones; United States; United States Food and Drug Administration; Young Adult

Topics: Benzamides; Biphenyl Compounds; Child; DNA Helicases; Enhancer of Zeste Homolog 2 Protein; Humans; Morpholines; Neoplasms; Nuclear Proteins; SMARCB1 Protein; Transcription Factors

EZH2 inhibitors that prevent trimethylation of histone lysine 27 (H3K27) are often limited to the treatment of a subset of hematological malignancies. In most solid tumors, EZH2 inhibitors induce reciprocal H3K27 acetylation that subsequently results in acquired drug resistance. The combination of EZH2 and BRD4 inhibitors to resensitize solid cancer cells to EZH2 inhibitors has proven to be effective, underlying the significance of developing dual inhibitors. Herein, we present the design, synthesis, and biological evaluation of first-in-class dual EZH2/BRD4 inhibitors. Our most promising compound, YM458, displays potent inhibitory activity against EZH2 and BRD4 and remarkable antiproliferative capacity against 11 solid cancer cell lines. Its in vivo therapeutic potential is validated in both lung cancer and pancreatic cancer xenograft tumor mice models, highlighting the potential of EZH2/BRD4 dual inhibitors to target a broad scope of EZH2 inhibitor-resistant solid tumors.

Topics: Animals; Cell Cycle Proteins; Cell Line, Tumor; Enhancer of Zeste Homolog 2 Protein; Histones; Humans; Mice; Neoplasms; Nuclear Proteins; Transcription Factors

Aberrance of epigenetic modification is one of the important factors leading to hematological malignancies. Histone deacetylase (HDAC) inhibitors and enhancers of zeste homologue 2 (EZH2) inhibitors are demonstrated to be significant epigenic modulators. Cocktail therapy of HDAC inhibitors and EZH2 inhibitors was demonstrated to be a promising strategy in hematological malignancies. We designed HDAC and EZH2 dual inhibitors based on the strong synergistic effect of SAHA and GSK126. Compound

Topics: Cell Line, Tumor; Cell Proliferation; Enhancer of Zeste Homolog 2 Protein; Epigenesis, Genetic; Hematologic Neoplasms; Histone Deacetylase 1; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Neoplasms

Sensitivity has been a key issue for Enhancer of zeste homolog 2 (EZH2) inhibitors in cancer therapy. The EZH2 inhibitor EPZ-6438 was first approved by the US Food and Drug Administration (FDA) in 2020. However, its inadequate anti-cancer activity in solid tumors limits its clinical application. In this study, we utilized the multiple cancer cell lines, which are less sensitive to the EZH2 inhibitor GSK126, combining animal model and clinical data to investigate the underlying mechanism.. IncuCyte S3 was used to explore the difference in the responsiveness of hematological tumor cells and solid tumor cells to GSK126. Transcriptome and metabolome of B16F10 cells after GSK126 treatment were analyzed and the distinct changes in the metabolic profile were revealed. Real-time quantitative PCR and western blot experiments were used to further verify the multi-omics data. ChIP-qPCR was performed to detected H3K27me3 enrichment of target genes. Finally, the anti-tumor effects of combining GSK126 and lipid metabolism drugs were observed with IncuCyte S3 platform, CCK-8 and animal model respectively.. We found that although the proliferative phenotype did not show strong difference upon treatment with GSK126, the transcriptome and metabolome changed profoundly. GSK126 treatment led to broad shifts in glucose, amino acid, and lipid metabolism. Lipid synthesis was strengthened manifested by the increasing abundance of unsaturated fatty acids. SCD1 and ELOVL2 were regulated by H3K27me3 at gene regulatory region, and upregulated by EZH2 knockdown and inhibitors. SCD1 knockdown increased cellular sensitivity to GSK126. Based on the findings above, the application of the combination with SCD1 inhibitor significantly attenuated the proliferation of cancer and increased the sensitivity to GSK126 by suppressing desaturation of fatty acids.. Dysregulated lipid metabolism can blunt the sensitivity of cancer cells to GSK126. These characteristics shed light on the novel combination therapy strategies to combat tumor resistance.. National Natural Science Foundation of China (No. 81672091, No.91749107 and No. 81972966).

Topics: Animals; Benzamides; Biphenyl Compounds; Cell Line, Tumor; Disease Models, Animal; Enhancer of Zeste Homolog 2 Protein; Enzyme Inhibitors; Humans; Lipid Metabolism; Lipogenesis; Morpholines; Neoplasms; Pyridones

Trimethylation of lysine 27 and dimethylation of lysine 9 of histone-H3 catalyzed by the histone methyltransferases EZH2 and G9a impede gene transcription in cancer. Our human bronchial epithelial (HBEC) pre-malignancy model studied the role of these histone modifications in transformation. Tobacco carcinogen transformed HBEC lines were characterized for cytosine DNA methylation, transcriptome reprogramming, and the effect of inhibiting EZH2 and G9a on the transformed phenotype. The effects of targeting EZH2 and G9a on lung cancer prevention was assessed in the A/J mouse lung tumor model.. Carcinogen exposure induced transformation and DNA methylation of 12-96 genes in the four HBEC transformed (T) lines that was perpetuated in malignant tumors. In contrast, 506 unmethylated genes showed reduced expression in one or more HBECTs with many becoming methylated in tumors. ChIP-on-chip for HBEC2T identified 327 and 143 genes enriched for H3K27me3 and H3K9me2. Treatment of HBEC2T and HBEC13T with DZNep, a lysine methyltransferase inhibitor depleted EZH2, reversed transformation, and induced transcriptional reprogramming. The EZH2 small molecule inhibitor EPZ6438 also affected transformation and expression in HBEC2T, while a G9a inhibitor, UNC0642 was ineffective. Genetic knock down of EZH2 dramatically reduced carcinogen-induced transformation of HBEC2. Only DZNep treatment prevented progression of hyperplasia to adenomas in the NNK mouse lung tumor model through reducing EZH2 and affecting the expression of genes regulating cell growth and invasion.. These studies demonstrate a critical role for EZH2 catalyzed histone modifications for premalignancy and its potential as a target for chemoprevention of lung carcinogenesis.

Topics: Adenosine; Adenosylhomocysteinase; Animals; Benzamides; Biphenyl Compounds; Cell Proliferation; Chromatin Assembly and Disassembly; CpG Islands; DNA Methylation; Enhancer of Zeste Homolog 2 Protein; Enzyme Inhibitors; Epigenesis, Genetic; Epithelial Cells; Female; Histone Code; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Histones; Humans; Lung Neoplasms; Mice; Morpholines; Neoplasms; Phenotype; Pyridones; Transcriptome

Epigenetic alterations contributing to malignancy have become a more prominent field of investigation over the past several years, as several hallmarks of cancer are substantially altered by changes in the epigenome. Enhancer of zeste homologue 2 (EZH2), an enzyme involved in silencing the transcription of various genes, is overexpressed or mutated in multiple cancers and can lead to proliferation of dedifferentiated cells. Both gain-of-function and loss-of-function mutations have been noted in hematologic cancers, with gain-of-function mutations prevalent among non-Hodgkin lymphomas. Tazemetostat is a first-in-class EZH2 inhibitor developed to target this overexpression. Phase I trials have shown it is generally well tolerated and efficacious in solid tumors as well as hematological malignancies. Tazemetostat was approved by the U.S. Food and Drug Administration (FDA) for use in epithelioid sarcoma in January 2020 on the basis of the results of a recent phase II trial, but with several clinical trials ongoing, the use of tazemetostat for hematological malignancies is a promising avenue for treatment.

Topics: Benzamides; Biphenyl Compounds; Clinical Trials as Topic; Enhancer of Zeste Homolog 2 Protein; Epigenesis, Genetic; Gene Silencing; Hematologic Neoplasms; Humans; Morpholines; Neoplasms; Pyridones

Although targeted therapies have revolutionized cancer treatment, overcoming acquired resistance remains a major clinical challenge. EZH2 inhibitors (EZH2i), EPZ-6438 and GSK126, are currently in the early stages of clinical evaluation and the first encouraging signs of efficacy have recently emerged in the clinic. To anticipate mechanisms of resistance to EZH2i, we used a forward genetic platform combining a mutagenesis screen with next generation sequencing technology and identified a hotspot of secondary mutations in the EZH2 D1 domain (Y111 and I109). Y111D mutation within the WT or A677G EZH2 allele conferred robust resistance to both EPZ-6438 and GSK126, but it only drove a partial resistance within the Y641F allele. EZH2 mutants required histone methyltransferase (HMT) catalytic activity and the polycomb repressive complex 2 (PRC2) components, SUZ12 and EED, to drive drug resistance. Furthermore, D1 domain mutations not only blocked the ability of EZH2i to bind to WT and A677G mutant, but also abrogated drug binding to the Y641F mutant. These data provide the first cellular validation of the mechanistic model underpinning the oncogenic function of WT and mutant EZH2. Importantly, our findings suggest that acquired-resistance to EZH2i may arise in WT and mutant EZH2 patients through a single mutation that remains targetable by second generation EZH2i.

Topics: Antineoplastic Agents; Benzamides; Biphenyl Compounds; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Enhancer of Zeste Homolog 2 Protein; Enzyme Inhibitors; HEK293 Cells; Humans; Indoles; Molecular Targeted Therapy; Morpholines; Mutation; Neoplasm Proteins; Neoplasms; Polycomb Repressive Complex 2; Protein Binding; Protein Structure, Tertiary; Pyridones; RNA Interference; Time Factors; Transcription Factors; Transfection

Inactivation of the switch/sucrose nonfermentable complex component SMARCB1 is extremely prevalent in pediatric malignant rhabdoid tumors (MRTs) or atypical teratoid rhabdoid tumors. This alteration is hypothesized to confer oncogenic dependency on EZH2 in these cancers. We report the discovery of a potent, selective, and orally bioavailable small-molecule inhibitor of EZH2 enzymatic activity, (N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-carboxamide). The compound induces apoptosis and differentiation specifically in SMARCB1-deleted MRT cells. Treatment of xenograft-bearing mice with (N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-carboxamide) leads to dose-dependent regression of MRTs with correlative diminution of intratumoral trimethylation levels of lysine 27 on histone H3, and prevention of tumor regrowth after dosing cessation. These data demonstrate the dependency of SMARCB1 mutant MRTs on EZH2 enzymatic activity and portend the utility of EZH2-targeted drugs for the treatment of these genetically defined cancers.

Topics: Animals; Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Cell Line, Tumor; Cell Proliferation; Drug Design; Enhancer of Zeste Homolog 2 Protein; Epigenesis, Genetic; Gene Expression Profiling; HEK293 Cells; Histones; Humans; Mice; Neoplasm Transplantation; Neoplasms; Polycomb Repressive Complex 2; Pyridines; Rhabdoid Tumor