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MYC amplification or overexpression is most common in Group 3 medulloblastomas and is positively associated with poor clinical outcomes. Protein arginine methyltransferase 5 (PRMT5) overexpression has been shown to be associated with tumorigenic MYC functions in cancers, particularly in brain cancers such as glioblastoma and medulloblastoma. PRMT5 regulates oncogenes, including MYC, that are often deregulated in medulloblastomas. However, the role of PRMT5-mediated post-translational modification in the stabilization of these oncoproteins remains poorly understood. The potential impact of PRMT5 inhibition on MYC makes it an attractive target in various cancers. PRMT5 inhibitors are a promising class of anti-cancer drugs demonstrating preclinical and preliminary clinical efficacies.
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 |
||
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 |
|
Bone |
Type I interferon signaling |
Altered expression (interferon gene) |
|
Prostate |
AR, ERG signaling |
Altered methylation (AR) |
|
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] |
Abbreviations: AKT-ERK, alpha serine/threonine-protein-extracellular-regulated kinase; AR, androgen receptor; E2F1, E2 promoter binding factor 1; EMT, epithelial–mesenchymal transition; ERG, ETS-related gene; FGFR3, fibroblast growth factor 3; FOXP1, forkhead box protein P1; FUS, fused in sarcoma; GSK3β-NF-kβ, glycogen synthase kinase; hnRNPA1, heterogeneous nuclear ribonucleoprotein A1; HTT, huntingtin protein; KLF4, Kruppel-like factor 4; LRP12, low-density lipoprotein receptor-related protein 12; LINC01138, long non-coding RNA; miR-99, microRNA99; mTOR, mammalian target of rapamycin; OCT4, octamer binding protein 4; PKB, protein kinase B; PDCD4, program cell death protein 4; SREBP, sterol regulatory element-binding protein; ZNF326, zinc finger protein 326.
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 |
|
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 |
|
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 |
|
LLY-283 (C220) |
|
SAM competitive |
22 nM |
Reduced acute graft versus host disease incidence in mice, antitumor effect in MPN xenografts |
|
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] |
Abbreviations: AML, acute myeloid leukemia; MCL, mantle cell lymphoma; MM, myelomonocytic leukemia; GBM, glioblastoma; TNBC, triple-negative breast cancer, PDX, patient-derived xenograft; DLBCL, diffuse large B cell lymphoma; CNS, central nervous system; MPN, myeloproliferative neoplasm; nM, nano molar; NA, not available; SAM, S-adenosylmethionine; MTA, methylthioadenosine.
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 |