PRMT5 as a Potential Therapeutic Target in MYC-Amplified Medulloblastoma
Abstract
:Simple Summary
Abstract
1. Introduction
2. PRMT5 Structure, Function, and Localization
2.1. Structure
2.2. Function
2.3. Localization
Organ | Cellular Function | Mechanism | References |
---|---|---|---|
Brain | Cell cycle progression, apoptosis | Altered expression and stability of MYC | [22] |
Phase separation | Methylation of FUS | [69] | |
GSK3β-NF-kβ signaling | Altered expression of E2F1 | [70] | |
HTT toxicity | Altered expression of HTT | [71] | |
AKT-ERK signaling, cell cycle progression | Altered expression of PTEN | [72] | |
Cell cycle progression, stemness | Altered RNA Splicing | [73,74] | |
mTOR signaling | Methylation (hnRNPA1) | [75] | |
DNA instability response | Altered expression of RNF168 | [76] | |
Cell migration, cell cycle progression, and apoptosis | Altered expression of LRP12 | [62] | |
AKT signaling and metastasis | Methylation of PKB | [77] | |
Lungs | Metastasis | Altered expression of EMT genes | [78] |
Metastasis | Altered expression of SHARPIN | [79] | |
Metastasis | Altered expression of FGFR3/miR-99 family | [80] | |
Metastasis | Methylation of KLF5 | [81] | |
Liver | Lipid metabolism | Methylation of SREBP | [47] |
ERK signaling | Altered expression of BTG2 | [82] | |
PRMY5 deprivation | PRMT5 activity of LINC01138 | [83] | |
WNT-β-Catenin signaling | Altered cofactor binding of LYRIC | [84] | |
Spleen | NA | Altered stability of MYC | [85] |
Pancreas | Glucose metabolism, cell cycle progression | Altered stability of MYC | [86,87] |
Bone | Type I interferon signaling | Altered expression (interferon gene) | [88,89] |
Prostate | AR, ERG signaling | Altered methylation (AR) | [90,91] |
Ovary | NA | Altered methylation (E2F1) | [92] |
Heart | Transcriptional activity | Methylation (GATA4) | [45] |
Breast | Stemness | Altered expression of C-MYC, KLF4, and OCT4 | [93] |
Stemness | Altered expression of FOXP1 | [94] | |
Metastasis and invasion | Altered expression of AKT genes | [78] | |
Metastasis and AKT signaling | Methylation of AKT | [95] | |
Cell cycle progression | Methylation of KLF4 | [96] | |
Cell migration | Methylation of ZNF326 | [97] | |
NA | Methylation of PDCD4 | [98] |
3. PRMT5 Association with MYC-Driven Medulloblastoma
4. Potential Inhibitors of PRMT5
4.1. JNJ-64619178
4.2. PF06939999
4.3. EPZ015666
4.4. GSK3326595
4.5. AMG 193
4.6. PRT543
4.7. PRT811
4.8. TNG908
4.9. MRTX1719
4.10. LLY 283
4.11. Compound1a
4.12. CMP5
4.13. GSK591
4.14. PRT382
4.15. JBI-778
4.16. SH3765
4.17. SCR6920
5. Future Perspective and Conclusions
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Compound Name | Structure | Function | IC50 In Vitro | In Vivo Activity | References |
---|---|---|---|---|---|
JNJ64619178 | Dual SAM/substrate competitive | 0.2 nM | Antitumor effect in lung cancer, AML, non-Hodgkin lymphoma cell line mouse xenograft | [108] | |
PF06939999 | SAM competitive | 3.3 nM | Antitumor effect in lung cancer | [109] | |
GSK3235025 EPZ015666 | Substrate competitive | 22 nM | Antitumor effect in MCL, MM, AML, GBM, and bladder cell line mouse xenografts and in a TNBC PDX mouse model | [110,111,112,113,114] | |
GSK591 (EPZ015866) | Substrate competitive | 4 nM | Antitumor effect in glioblastoma | [110] | |
GSK3326595 | Substrate competitive | 6.2 nM | Antitumor effect in non-Hodgkin lymphoma cell line mouse xenograft and antitumor effect in a DLBCL PDX mouse model | [115,116,117,118] | |
AMG 193 | Structure undisclosed | MTA cooperative inhibitor | NA | Antitumor effect on advanced/metastatic solid tumors | [119] |
PRT543 | SAM competitive | 10.8 nM | Antitumor effect on advanced solid tumors and hematologic malignancies | [120] | |
PRT382 | Structure undisclosed | SAM competitive | 2.8 nM | Antitumor effect on hematological tumors | [85] |
PRT811 | Structure undisclosed | SAM competitive | 3.9 nM | Antitumor effect on advanced solid tumor, Glioblastoma, CNS Lymphoma | [121] |
TNG908 | Structure undisclosed | MTA cooperative inhibitor | 110 nM | Antitumor effect on Glioblastoma, | [122] |
MRTX1719 | PRMT5–MTA complex inhibitor, MTA competitive | 12 nM | Antitumor effect on solid tumor | [123,124] | |
LLY-283 (C220) | SAM competitive | 22 nM | Reduced acute graft versus host disease incidence in mice, antitumor effect in MPN xenografts | [74,125,126] | |
Compound1a | Allosteric modulator | 16 nM | Antitumor effect in breast cancer | [127] | |
CMP5 | Structure undisclosed | SAM competitive | 25 µM | Antitumor effect in breast cancer and glioblastoma | [72] |
JBI-778 | Structure undisclosed | Substrate competitive | 27 to 700 nM | Antitumor effect in glioblastoma | [128] |
SH3765 | Structure undisclosed | Substrate competitive | NA | Antitumor effect on advanced malignant tumors, including solid tumors and non-Hodgkin lymphoma | [129] |
SCR6920 | Structure undisclosed | Substrate competitive | NA | Antitumor effect on advanced malignant tumor including solid tumor and non-Hodgkin lymphoma | [129] |
ClinicalTrials.gov Identifier | Name of Inhibitor | Status | Disease |
---|---|---|---|
NCT03573310 | JNJ64619178 | Phase I | Neoplasm solid tumors, non-Hodgkin lymphoma, and myelodysplastic syndrome |
NCT03854227 | PF06939999 | Phase I | Advance and metastatic solid tumors |
NCT03614728 | GSK3326595 | Phase I and II | Metastatic solid tumors and acute myeloid leukemia |
NCT02783300 | GSK3326595 | Phase I | Solid tumors and non-Hodgkin lymphoma |
NCT04676516 | GSK3326595 | Phase II | Early-stage breast cancer |
NCT03886831 | PRT543 | Phase I | Advanced solid tumors and hematological malignancies |
NCT05275478 | TNG908 | Phase I and II (recruiting) | Locally advanced solid tumors |
NCT04089449 | PRT811 | Phase I (recruiting) | Advanced solid tumors, recurrent glioma, and CNS lymphoma |
NCT05245500 | MRTX1719 | Phase I and II (recruiting) | Mesothelioma, NSCLC, malignant peripheral nerve sheath tumors, solid tumors, and pancreatic adenocarcinoma |
NCT05094336 | AMG 193 | Phase I and II (recruiting) | Advanced MTAP-null solid tumors |
NCT05528055 | SCR6920 | Phase I (recruiting) | Advanced malignant tumors |
NCT05015309 | SH3765 | Phase I (not yet Recruiting) | Advanced malignant tumors |
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Share and Cite
Kumar, D.; Jain, S.; Coulter, D.W.; Joshi, S.S.; Chaturvedi, N.K. PRMT5 as a Potential Therapeutic Target in MYC-Amplified Medulloblastoma. Cancers 2023, 15, 5855. https://doi.org/10.3390/cancers15245855
Kumar D, Jain S, Coulter DW, Joshi SS, Chaturvedi NK. PRMT5 as a Potential Therapeutic Target in MYC-Amplified Medulloblastoma. Cancers. 2023; 15(24):5855. https://doi.org/10.3390/cancers15245855
Chicago/Turabian StyleKumar, Devendra, Stuti Jain, Don W. Coulter, Shantaram S. Joshi, and Nagendra K. Chaturvedi. 2023. "PRMT5 as a Potential Therapeutic Target in MYC-Amplified Medulloblastoma" Cancers 15, no. 24: 5855. https://doi.org/10.3390/cancers15245855
APA StyleKumar, D., Jain, S., Coulter, D. W., Joshi, S. S., & Chaturvedi, N. K. (2023). PRMT5 as a Potential Therapeutic Target in MYC-Amplified Medulloblastoma. Cancers, 15(24), 5855. https://doi.org/10.3390/cancers15245855