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An overview of the development of EED inhibitors to disable the PRC2 function.

ABSTRACT: Polycomb repressive complex 2 (PRC2) catalyzes the methylation of histone H3 lysine 27 (H3K27) and the enrichment of its catalytic product H3K27me3 is responsible for the silencing of tumor suppressor genes and the blocking of transcripts related to immunity and cell terminal differentiation. Aberrations of PRC2 components, such as mutation and overexpression, have been observed in various cancers, which makes PRC2 a potential therapeutic target for cancer. Up to now, targeting the enhancer of zeste homolog 2 (EZH2), the catalytic subunit of PRC2, represents the main strategy in the development of PRC2 inhibitors. Although significant progress has been made, new problems also emerge, e.g. the drug resistance caused by secondary mutations. In recent years, more and more efforts have shifted to another new strategy - targeting embryonic ectoderm development (EED) to disrupt its major interactions with other components, which are necessary to the PRC2 function, and some promising results have been obtained. This review summarizes the recent development of EED inhibitors as possible chemotherapy for cancer treatment, which could help accelerate future related research work.

SUBMITTER: Liu KL

PROVIDER: S-EPMC8792826 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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An overview of the development of EED inhibitors to disable the PRC2 function.

Liu Kai-Lu KL Zhu Kongkai K Zhang Hua H

RSC medicinal chemistry 20211021 1

Polycomb repressive complex 2 (PRC2) catalyzes the methylation of histone H3 lysine 27 (H3K27) and the enrichment of its catalytic product H3K27me3 is responsible for the silencing of tumor suppressor genes and the blocking of transcripts related to immunity and cell terminal differentiation. Aberrations of PRC2 components, such as mutation and overexpression, have been observed in various cancers, which makes PRC2 a potential therapeutic target for cancer. Up to now, targeting the enhancer of z ...[more]

PMID: 35224495

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Project description:Dysregulated cell division, which leads to aberrant cell proliferation, is one of the key hallmarks of cancer. Therefore, therapeutic targets that block cell division would be effective for cancer treatment. Cell division is mainly controlled by a complex composed of cyclin and cyclin dependent kinases (CDKs). To date, the CDK inhibitors (CDKIs), specifically the ones that block the enzyme activity of CDK4 and CDK6 (CDK4/6), have been approved by FDA for the treatment of metastatic hormone receptor positive breast cancer. However, due to the non-selectivity and significant toxicity, most of the first generation CDK inhibitors (so called pan-CDK inhibitors that target several CDKs), have not been approved for clinical application. Despite this, great efforts and progress have been made to enable pan-CDK inhibitors application in the clinical setting. Notably, the development of combination therapy strategies in recent years has made it possible to reduce the toxicity and side effects of pan-CDK inhibitors. Thus, as a combination therapy approach, pan-CDK inhibitors regain great potential in clinical application. In this review, we introduced the CDK family members and discussed their major functions in cell cycle controlling. Then, we summarized the research progress regarding CDK inhibitors, especially those other than CDK4/6 inhibitors. We reviewed first-generation pan-CDKIs Flavopiridol and Roscovitine, and second-generation CDKIs Dinaciclib, P276-00, AT7519, TG02, Roniciclib, RGB-286638 by focusing on their developing stages, clinical trials and targeting cancers. The specific CDKIs, which targets to increase specificity and decrease the side effects, were also discussed. These CDKIs include CDK4/6, CDK7, CDK9, and CDK12/13 inhibitors. Finally, the efficacy and discrepancy of combination therapy with CDK inhibitors and PD1/PDL1 antibodies were analyzed, which might give insights into the development of promising strategy for cancer treatment.

Dataset Information

An overview of the development of EED inhibitors to disable the PRC2 function.

Publications

An overview of the development of EED inhibitors to disable the PRC2 function.

Similar Datasets

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