Protein arginine methyltransferases and hepatocellular carcinoma: A review

Yu, Lei; Han, Ping; Tian, Dean

doi:10.1016/j.tranon.2021.101194

Cited by 8 publications

(6 citation statements)

References 100 publications

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“…Compared to other PRMTs, PRMT7 and PRMT9 are relatively underinvestigated and, although they have been recently identified as potential therapeutic targets for the treatment of various diseases, including different types of cancer, ,,− much is still to be understood on their biological roles, as well as on the structural requirements that could drive the development of selective modulators of their methyltransferase activity.…”

Section: Discussionmentioning

confidence: 99%

“…15 Seemingly, most of the biological roles of PRMT9 remain to be further defined along with its substrates. 13 Nonetheless, PRMT9 has been identified as a potential target for treating hepatocellular carcinoma, 22,23 for suppressing acute myeloid leukemia maintenance, 24 and it is required for androgen-dependent proliferation of LNCaP prostate cancer cells. 25 It has been reported to play a role in the regulation of alternative splicing.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Nonetheless, PRMT9 has been identified as a potential target for treating hepatocellular carcinoma, , for suppressing acute myeloid leukemia maintenance, and it is required for androgen-dependent proliferation of LNCaP prostate cancer cells . It has been reported to play a role in the regulation of alternative splicing. , Very recently, it has been shown that PRMT9 attenuates activation of mitochondrial antiviral signaling protein (MAVS) through arginine methylation (R41 and R43), thus reducing innate antiviral immune response …”

Section: Introductionmentioning

confidence: 99%

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Identification of a Protein Arginine Methyltransferase 7 (PRMT7)/Protein Arginine Methyltransferase 9 (PRMT9) Inhibitor

Feoli,

Iannelli,

Cipriano

et al. 2023

J. Med. Chem.

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Less studied than the other protein arginine methyltransferase isoforms, PRMT7 and PRMT9 have recently been identified as important therapeutic targets. Yet, most of their biological roles and functions are still to be defined, as well as the structural requirements that could drive the identification of selective modulators of their activity. We recently described the structural requirements that led to the identification of potent and selective PRMT4 inhibitors spanning both the substrate and the cosubstrate pockets. The reanalysis of the data suggested a PRMT7 preferential binding for shorter derivatives and prompted us to extend these structural studies to PRMT9. Here, we report the identification of the first potent PRMT7/9 inhibitor and its binding mode to the two PRMT enzymes. Label-free quantification mass spectrometry confirmed significant inhibition of PRMT activity in cells. We also report the setup of an effective AlphaLISA assay to screen small molecule inhibitors of PRMT9.

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Section: Discussionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of a Protein Arginine Methyltransferase 7 (PRMT7)/Protein Arginine Methyltransferase 9 (PRMT9) Inhibitor

Feoli,

Iannelli,

Cipriano

et al. 2023

J. Med. Chem.

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“…There are three subclasses of protein arginine methyltransferases (PRMTs): (i) asymmetric dimethylarginine (ADMA), (ii) symmetric dimethylarginine (SDMA) and (iii) monomethyl arginine (MMA) ( 103 ). All PRMTs deposit monomethyl marks, but symmetrical or asymmetrical dimethylation is dependent on the specific PRMT class, adding another layer of complexity to the signaling ( 104 ). PRMTs dynamically contribute to the co-activation or co-repression of genes by promoting the recruitment of transcription factors or other epigenetic complexes ( 105 ).…”

Section: Interplay Of Pp2a and Chromatin Remodeling Complexesmentioning

confidence: 99%

PP2A and cancer epigenetics: a therapeutic opportunity waiting to happen

Tinsley

Allen-Petersen

2022

NAR Cancer

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The epigenetic state of chromatin is altered by regulators which influence gene expression in response to environmental stimuli. While several post-translational modifications contribute to chromatin accessibility and transcriptional programs, our understanding of the role that specific phosphorylation sites play is limited. In cancer, kinases and phosphatases are commonly deregulated resulting in increased oncogenic signaling and loss of epigenetic regulation. Aberrant epigenetic states are known to promote cellular plasticity and the development of therapeutic resistance in many cancer types, highlighting the importance of these mechanisms to cancer cell phenotypes. Protein Phosphatase 2A (PP2A) is a heterotrimeric holoenzyme that targets a diverse array of cellular proteins. The composition of the PP2A complex influences its cellular targets and activity. For this reason, PP2A can be tumor suppressive or oncogenic depending on cellular context. Understanding the nuances of PP2A regulation and its effect on epigenetic alterations can lead to new therapeutic avenues that afford more specificity and contribute to the growth of personalized medicine in the oncology field. In this review, we summarize the known PP2A-regulated substrates and potential phosphorylation sites that contribute to cancer cell epigenetics and possible strategies to therapeutically leverage this phosphatase to suppress tumor growth.

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“…The following table shows representative compounds tested for PRMT5 inhibition and the biological data obtained from testing the representative examples. …”

Section: Important Compound Classesmentioning

confidence: 99%

Tricyclic Carboxamide Derivatives as PRMT5 Inhibitors for Treating Cancer

Sabnis¹

2022

ACS Med. Chem. Lett.

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of gene expression is an important biological determinant of protein production and cellular differentiation and plays a significant pathogenic role in several human diseases. Epigenetic regulation involves heritable modification of genetic material without changing its nucleotide sequence. Typically, epigenetic regulation is mediated by selective and reversible modification (e.g., methylation) of DNA and proteins (e.g., histones) that control the conformational transition between transcriptionally active and inactive states of chromatin. These covalent modifications can be controlled by enzymes such as methyltransferases (e.g., protein arginine N-methyltransferase 5 (PRMT5)), many of which are associated with specific genetic alterations that can cause human disease. PRMT5 plays a role in diseases such as proliferative disorders, metabolic disorders, and blood disorders.The homozygous deletion of tumor suppressor genes is a key driver of cancer, frequently resulting in the collateral loss of passenger genes located in close genomic proximity to the tumor suppressor. Deletion of these passenger genes can create therapeutically tractable vulnerabilities that are specific to tumor cells. Deletion of methylthioadenosine phosphorylase R 1 = H, halo, optionally substituted C 1−3 alkyl, wherein substituents are selected from halo or CN, optionally substituted -O-C 1−3 alkyl, wherein substituents are selected from halo, -C(O)OC 1−3 alkyl, wherein C 1−3 alkyl can be optionally substituted with halo, and morpholinyl; and R 2 = optionally substituted C 1−8 alkyl, wherein substituents are selected from halo, OH, NH 2 , -O-C 1−3 alkyl, or CN, or five-or six-membered cycle or heterocycle, optionally substituted with OH or NH 2 .Key Structures.Biological Assay. The HTC116 MTAP null proliferation assay was performed. The compounds described in this application were tested for their ability to inhibit PRMT5. The PRMT5 IC 50 (μM) are shown in the table below. Biological Data. The following table shows representative compounds tested for PRMT5 inhibition and the biological data obtained from testing the representative examples. Claims. Total claims: 24 Compound claims: 21 Pharmaceutical composition claims: 1 Method of treatment claims: 2 ■ AUTHOR INFORMATION

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Protein arginine methyltransferases and hepatocellular carcinoma: A review

Cited by 8 publications

References 100 publications

Identification of a Protein Arginine Methyltransferase 7 (PRMT7)/Protein Arginine Methyltransferase 9 (PRMT9) Inhibitor

Identification of a Protein Arginine Methyltransferase 7 (PRMT7)/Protein Arginine Methyltransferase 9 (PRMT9) Inhibitor

PP2A and cancer epigenetics: a therapeutic opportunity waiting to happen

Tricyclic Carboxamide Derivatives as PRMT5 Inhibitors for Treating Cancer

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