An updated patent review of protein arginine N-methyltransferase inhibitors (2019–2022)

Dong, Junde; Duan, Jilong; Hui, Zi; Garrido, Carmen; Deng, Zhangshuang; Xie, Tian; Ye, Xiang‐Yang

doi:10.1080/13543776.2022.2163162

Cited by 15 publications

(11 citation statements)

References 43 publications

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“…Among the hits from the screen, we focused on Prmt5, as its silencing presented the strongest phenotype. Prmt5 belongs to the evolutionarily conserved arginine methyltransferase protein family [15]. It catalyzes the transfer of a methyl group from S-adenosyl-methionine to the guanidino nitrogen atoms of arginine as monomethylation and symmetric demethylation [15].…”

Section: Discussionmentioning

confidence: 99%

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Genetic Screen Identified Prmt5 as a Neuroprotection Target against Cerebral Ischemia

Wang

et al. 2023

Preprint

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Epigenetic regulators present novel opportunities for both ischemic stroke research and therapeutic interventions. While previous work has implicated that they may provide neuroprotection by potentially influencing coordinated sets of genes and pathways, most of them remains largely uncharacterized in ischemic conditions. In this study, we used the oxygen-glucose deprivation (OGD) model in the immortalized mouse hippocampal neuronal cell line HT-22 and carried out an RNAi screen on epigenetic regulators. We identified Prmt5 as a novel negative regulator of neuronal cell survival after OGD, which presented a phenotype of translocation from the cytosol to the nucleus upon oxygen and energy depletion both in vitro and in vivo. Prmt5 bound to the chromatin and a large number of promoter regions to repress downstream gene expression. Silencing Prmt5 significantly dampened the OGD-induced changes for a large-scale of genes, and gene ontology analysis showed that Prmt5-target genes were highly enriched for Hedgehog signaling. Encouraged by the above observation, we treated mice with middle cerebral artery occlusion (MCAO) with the Prmt5 inhibitor EPZ015666 and found that Prmt5 inhibition sustain protection against neuronal death in vivo. Together, our findings revealed a novel epigenetic mechanism of Prmt5 in cerebral ischemia and uncovered a potential target for neuroprotection.

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Section: Discussionmentioning

confidence: 99%

“…Prmt5 belongs to the evolutionarily conserved arginine methyltransferase protein family [15]. It catalyzes the transfer of a methyl group from S-adenosyl-methionine to the guanidino nitrogen atoms of arginine as monomethylation and symmetric demethylation [15]. Prmt5 has been implicated in various developmental processes and diseases [16].…”

Section: Discussionmentioning

confidence: 99%

Genetic Screen Identified Prmt5 as a Neuroprotection Target against Cerebral Ischemia

Wang

et al. 2023

Preprint

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“…Preclinical and clinical studies have shown that high expression of PRMT5 is observed in various solid tumors and hematological malignancies, such as melanoma, lung, glioblastoma, pancreatic, prostate cancer, colorectal carcinoma, leukemia, and lymphoma. − In addition, increased PRMT5 expression is closely associated with poor overall survival and correlated with tumor metastasis. − Owing to the critical roles that PRMT5 plays in cancer initiation and progression, interest has been increasing in the development of novel, potent and selective inhibitors for PRMT5 targeted therapy. − In the past 5 years, many new advances have been made toward the development of PRMT5 inhibitors targeting the catalytic methyltransferase domain, which are defined as the first-generation PRMT5 inhibitors . According to their different binding pockets, the first-generation PRMT5 inhibitors can be classified into two types.…”

Section: Introductionmentioning

confidence: 99%

Targeting Arginine Methyltransferase PRMT5 for Cancer Therapy: Updated Progress and Novel Strategies

Zheng

et al. 2023

J. Med. Chem.

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As a predominant type II protein arginine methyltransferase, PRMT5 plays critical roles in various normal cellular processes by catalyzing the mono- and symmetrical dimethylation of a wide range of histone and nonhistone substrates. Clinical studies have revealed that high expression of PRMT5 is observed in different solid tumors and hematological malignancies and is closely associated with cancer initiation and progression. Accordingly, PRMT5 is becoming a promising anticancer target and has received great attention in both the pharmaceutical industry and the academic community. In this Perspective, we comprehensively summarize recent advances in the development of first-generation PRMT5 enzymatic inhibitors and highlight novel strategies targeting PRMT5 in the past 5 years. We also discuss the challenges and opportunities of PRMT5 inhibition, with the aim of shedding light on future PRMT5 drug discovery.

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“…Arginine methylation is one form of modification with pleiotropic effects including DNA damage repair, splicing, cell cycle regulation, signal transduction, etc. [ 4 , 5 , 6 , 7 , 8 ]. Nine different protein methyltransferases have been identified [ 5 ] and are generally divided into three groups: (1) monomethylators that add one methyl group onto arginine; (2) symmetric dimethylators that methylate both arginine side-chain nitrogen groups, also known as Type II; and (3) asymmetric dimethylators that methylate the same arginine side-chain nitrogen group, also known as Type I [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…A PubMed search with the prompt “PRMT5 cancer” retrieves over 500 articles highlighting the importance of this gene in cancer. Consequently, PRMT5 small molecule inhibitors are already in clinical trials [ 6 , 15 ]. High expression of PRMT5 correlating with poor prognosis has been detected in many cancers, suggesting that PRMT5 has oncogenic function [ 26 , 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

Protein Arginine Methyltransferase 5 (PRMT5) Mutations in Cancer Cells

Rasheed

Bouley

Yoder

et al. 2023

IJMS

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Arginine methylation is a form of posttranslational modification that regulates many cellular functions such as development, DNA damage repair, inflammatory response, splicing, and signal transduction, among others. Protein arginine methyltransferase 5 (PRMT5) is one of nine identified methyltransferases, and it can methylate both histone and non-histone targets. It has pleiotropic functions, including recruitment of repair machinery to a chromosomal DNA double strand break (DSB) and coordinating the interplay between repair and checkpoint activation. Thus, PRMT5 has been actively studied as a cancer treatment target, and small molecule inhibitors of its enzymatic activity have already been developed. In this report, we analyzed all reported PRMT5 mutations appearing in cancer cells using data from the Catalogue of Somatic Mutations in Cancers (COSMIC). Our goal is to classify mutations as either drivers or passengers to understand which ones are likely to promote cellular transformation. Using gold standard artificial intelligence algorithms, we uncovered several key driver mutations in the active site of the enzyme (D306H, L315P, and N318K). In silico protein modeling shows that these mutations may affect the affinity of PRMT5 for S-adenosylmethionine (SAM), which is required as a methyl donor. Electrostatic analysis of the enzyme active site shows that one of these mutations creates a tunnel in the vicinity of the SAM binding site, which may allow interfering molecules to enter the enzyme active site and decrease its activity. We also identified several non-coding mutations that appear to affect PRMT5 splicing. Our analyses provide insights into the role of PRMT5 mutations in cancer cells. Additionally, since PRMT5 single molecule inhibitors have already been developed, this work may uncover future directions in how mutations can affect targeted inhibition.

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An updated patent review of protein arginine N-methyltransferase inhibitors (2019–2022)

Cited by 15 publications

References 43 publications

Genetic Screen Identified Prmt5 as a Neuroprotection Target against Cerebral Ischemia

Genetic Screen Identified Prmt5 as a Neuroprotection Target against Cerebral Ischemia

Targeting Arginine Methyltransferase PRMT5 for Cancer Therapy: Updated Progress and Novel Strategies

Protein Arginine Methyltransferase 5 (PRMT5) Mutations in Cancer Cells

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