gsk-2816126 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

Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the Polycomb repressive complex 2, inhibits gene expression through methylation on lysine 27 of histone H3. EZH2 regulates normal hematopoietic stem cell self-renewal and differentiation. EZH2 also controls normal B cell differentiation. EZH2 deregulation has been described in many cancer types including hematological malignancies. Specific small molecules have been recently developed to exploit the oncogenic addiction of tumor cells to EZH2. Their therapeutic potential is currently under evaluation. This review summarizes the roles of EZH2 in normal and pathologic hematological processes and recent advances in the development of EZH2 inhibitors for the personalized treatment of patients with hematological malignancies.

Topics: Adenosine; B-Lymphocytes; Cell Differentiation; Cell Proliferation; Enhancer of Zeste Homolog 2 Protein; Epigenesis, Genetic; Ethylenediamines; Gene Expression Regulation; Hematologic Neoplasms; Hematopoiesis; Hematopoietic Stem Cells; Histones; Humans; Indoles; Methylation; Polycomb Repressive Complex 2; Precision Medicine; Pyrazoles; Pyridones