epz-6438 and Hematologic-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

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

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