Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTR1D7X)

• DTT Name: Protein arginine methyltransferase 5 (PRMT5)
• Synonyms: Shk1 kinase-binding protein 1 homolog; SKB1Hs; SKB1 homolog; SKB1; Protein arginine N-methyltransferase 5; Jak-binding protein 1; JBP1; IBP72; Histone-arginine N-methyltransferase PRMT5; HRMT1L5; 72 kDa ICln-binding protein
• Gene Name: PRMT5
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Methyltransferase
• UniProt ID: ANM5_HUMAN
• TTD ID: T82665
• EC Number: EC 2.1.1.320
• Sequence:
  MAAMAVGGAGGSRVSSGRDLNCVPEIADTLGAVAKQGFDFLCMPVFHPRFKREFIQEPAK
  NRPGPQTRSDLLLSGRDWNTLIVGKLSPWIRPDSKVEKIRRNSEAAMLQELNFGAYLGLP
  AFLLPLNQEDNTNLARVLTNHIHTGHHSSMFWMRVPLVAPEDLRDDIIENAPTTHTEEYS
  GEEKTWMWWHNFRTLCDYSKRIAVALEIGADLPSNHVIDRWLGEPIKAAILPTSIFLTNK
  KGFPVLSKMHQRLIFRLLKLEVQFIITGTNHHSEKEFCSYLQYLEYLSQNRPPPNAYELF
  AKGYEDYLQSPLQPLMDNLESQTYEVFEKDPIKYSQYQQAIYKCLLDRVPEEEKDTNVQV
  LMVLGAGRGPLVNASLRAAKQADRRIKLYAVEKNPNAVVTLENWQFEEWGSQVTVVSSDM
  REWVAPEKADIIVSELLGSFADNELSPECLDGAQHFLKDDGVSIPGEYTSFLAPISSSKL
  YNEVRACREKDRDPEAQFEMPYVVRLHNFHQLSAPQPCFTFSHPNRDPMIDNNRYCTLEF
  PVEVNTVLHGFAGYFETVLYQDITLSIRPETHSPGMFSWFPILFPIKQPITVREGQTICV
  RFWRCSNSKKVWYEWAVTAPVCSAIHNPTGRSYTIGL
• Function: Specifically mediates the symmetrical dimethylation of arginine residues in the small nuclear ribonucleoproteins Sm D1 (SNRPD1) and Sm D3 (SNRPD3); such methylation being required for the assembly and biogenesis of snRNP core particles. Methylates SUPT5H and may regulate its transcriptional elongation properties. Mono- and dimethylates arginine residues of myelin basic protein (MBP) in vitro. May play a role in cytokine-activated transduction pathways. Negatively regulates cyclin E1 promoter activity and cellular proliferation. Methylates histone H2A and H4 'Arg-3' during germ cell development. Methylates histone H3 'Arg-8', which may repress transcription. Methylates the Piwi proteins (PIWIL1, PIWIL2 and PIWIL4), methylation of Piwi proteins being required for the interaction with Tudor domain-containing proteins and subsequent localization to the meiotic nuage. Methylates RPS10. Attenuates EGF signaling through the MAPK1/MAPK3 pathway acting at 2 levels. First, monomethylates EGFR; this enhances EGFR 'Tyr-1197' phosphorylation and PTPN6 recruitment, eventually leading to reduced SOS1 phosphorylation. Second, methylates RAF1 and probably BRAF, hence destabilizing these 2 signaling proteins and reducing their catalytic activity. Required for induction of E-selectin and VCAM-1, on the endothelial cells surface at sites of inflammation. Methylates HOXA9. Methylates and regulates SRGAP2 which is involved in cell migration and differentiation. Acts as a transcriptional corepressor in CRY1-mediated repression of the core circadian component PER1 by regulating the H4R3 dimethylation at the PER1 promoter. Methylates GM130/GOLGA2, regulating Golgi ribbon formation. Methylates H4R3 in genes involved in glioblastomagenesis in a CHTOP- and/or TET1-dependent manner. Symmetrically methylates POLR2A, a modification that allows the recruitment to POLR2A of proteins including SMN1/SMN2 and SETX. This is required for resolving RNA-DNA hybrids created by RNA polymerase II, that form R-loop in transcription terminal regions, an important step in proper transcription termination. Along with LYAR, binds the promoter of gamma-globin HBG1/HBG2 and represses its expression. Symmetrically methylates NCL. Methylates TP53; methylation might possibly affect TP53 target gene specificity. Arginine methyltransferase that can both catalyze the formation of omega-N monomethylarginine (MMA) and symmetrical dimethylarginine (sDMA), with a preference for the formation of MMA.
• Reactome Pathway:
  RMTs methylate histone arginines (R-HSA-3214858)
  Regulation of TP53 Activity through Methylation (R-HSA-6804760)
  snRNP Assembly (R-HSA-191859)
• BioCyc Pathway: MetaCyc:HS02092-MON

Molecular Interaction Atlas (MIA) of This DTT

6 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AMG 193	DMU9K8N	Aggressive cancer	2A00-2F9Z	Phase 2	[2]
GSK3326595	DMJRD7A	Breast cancer	2C60-2C65	Phase 2	[1]
JNJ-64619178	DMDBW2N	Myelodysplastic syndrome	2A37	Phase 1	[3]
PF-06939999	DM7BOFR	Solid tumour/cancer	2A00-2F9Z	Phase 1	[4]
PRT543	DMHNZ3U	Hematologic tumour	2B33.Y	Phase 1	[5]
PRT811	DMW3MCX	Glioma	2A00.0	Phase 1	[6]

3 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
cmp5	DMBT2ZW	Discovery agent	N.A.	Investigative	[7]
DS-437	DME3WBQ	Discovery agent	N.A.	Investigative	[8]
EPZ015666	DM3INX7	Discovery agent	N.A.	Investigative	[9]

References

• [1] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [2] AMG 193 Effective in Multiple Tumor Types. Cancer Discov. 2023 Dec 12;13(12):2492.
• [3] A patent review of arginine methyltransferase inhibitors (2010-2018). Expert Opin Ther Pat. 2019 Feb;29(2):97-114.
• [4] National Cancer Institute Drug Dictionary (drug name PF-06939999).
• [5] Clinical pipeline report, company report or official report of Prelude Therapeutics.
• [6] Clinical pipeline report, company report or official report of Prelude Therapeutics.
• [7] Selective inhibition of protein arginine methyltransferase 5 blocks initiation and maintenance of B-cell transformation. Blood. 2015 Apr 16;125(16):2530-43.
• [8] Discovery of a Dual PRMT5-PRMT7 Inhibitor. ACS Med Chem Lett. 2015 Mar 2;6(4):408-12.
• [9] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1256).