PRMT5

Summary

PRMT5 (protein arginine methyltransferase 5, HGNC:10894) is a protein-coding gene on chromosome 14q11.2, encoding Protein arginine N-methyltransferase 5 (O14744). 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. It is a common-essential gene (DepMap: required in 94.9% of cancer cell lines).

This gene encodes an enzyme that belongs to the methyltransferase family. The encoded protein catalyzes the transfer of methyl groups to the amino acid arginine, in target proteins that include histones, transcriptional elongation factors and the tumor suppressor p53. This gene plays a role in several cellular processes, including transcriptional regulation, and the assembly of small nuclear ribonucleoproteins. A pseudogene of this gene has been defined on chromosome 4. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 10419 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 57 total
• Druggable target: yes — 5 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 94.9% of screened cell lines (common-essential)
• MANE Select transcript: NM_006109

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10894
Approved symbol	PRMT5
Name	protein arginine methyltransferase 5
Location	14q11.2
Locus type	gene with protein product
Status	Approved
Aliases	SKB1Hs
Ensembl gene	ENSG00000100462
Ensembl biotype	protein_coding
OMIM	604045
Entrez	10419

Gene structure

Transcript identifiers

Ensembl transcripts: 31 — 20 protein_coding, 4 protein_coding_CDS_not_defined, 4 retained_intron, 3 nonsense_mediated_decay

ENST00000216350, ENST00000324366, ENST00000397440, ENST00000397441, ENST00000421938, ENST00000454731, ENST00000476175, ENST00000553417, ENST00000553502, ENST00000553550, ENST00000553641, ENST00000553787, ENST00000553897, ENST00000553915, ENST00000554716, ENST00000554867, ENST00000554910, ENST00000555454, ENST00000555530, ENST00000556032, ENST00000556043, ENST00000556426, ENST00000556616, ENST00000557015, ENST00000557415, ENST00000557443, ENST00000557758, ENST00000627278, ENST00000903535, ENST00000903536, ENST00000948386

RefSeq mRNA: 6 — MANE Select: NM_006109 NM_001039619, NM_001282953, NM_001282954, NM_001282955, NM_001282956, NM_006109

CCDS: CCDS41922, CCDS61394, CCDS61395, CCDS61396, CCDS9579

Canonical transcript exons

ENST00000324366 — 17 exons

Exon	Start	End
ENSE00002438513	22920529	22921056
ENSE00002524725	22929252	22929376
ENSE00003480646	22928126	22928211
ENSE00003485706	22928497	22928615
ENSE00003490969	22926506	22926555
ENSE00003493346	22924270	22924392
ENSE00003504639	22922176	22922240
ENSE00003506566	22927526	22927660
ENSE00003512765	22922742	22922835
ENSE00003567613	22923051	22923160
ENSE00003580528	22924008	22924183
ENSE00003588053	22922443	22922559
ENSE00003616383	22924632	22924709
ENSE00003629689	22926133	22926296
ENSE00003649944	22924479	22924537
ENSE00003665575	22926702	22926814
ENSE00003672945	22924879	22925040

Expression profiles

Bgee: expression breadth ubiquitous, 278 present calls, max score 96.95.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.6296 / max 155.4802, expressed in 1800 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
142268	24.3493	1800
142267	0.1505	64
142266	0.1299	55

Top tissues by expression

292 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	96.95	gold quality
amniotic fluid	UBERON:0000173	96.22	gold quality
ganglionic eminence	UBERON:0004023	95.67	gold quality
embryo	UBERON:0000922	95.52	gold quality
lower esophagus mucosa	UBERON:0035834	95.39	gold quality
cortical plate	UBERON:0005343	95.04	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	94.97	gold quality
right uterine tube	UBERON:0001302	94.90	gold quality
left ovary	UBERON:0002119	94.60	gold quality
right ovary	UBERON:0002118	94.57	gold quality
esophagus mucosa	UBERON:0002469	94.51	gold quality
gastrocnemius	UBERON:0001388	94.43	gold quality
mucosa of transverse colon	UBERON:0004991	94.39	gold quality
islet of Langerhans	UBERON:0000006	94.31	gold quality
left uterine tube	UBERON:0001303	94.29	gold quality
muscle of leg	UBERON:0001383	94.17	gold quality
right testis	UBERON:0004534	94.04	gold quality
stromal cell of endometrium	CL:0002255	94.00	gold quality
right lobe of thyroid gland	UBERON:0001119	94.00	gold quality
ovary	UBERON:0000992	93.93	gold quality
left testis	UBERON:0004533	93.84	gold quality
esophagus	UBERON:0001043	93.70	gold quality
left lobe of thyroid gland	UBERON:0001120	93.66	gold quality
rectum	UBERON:0001052	93.65	gold quality
body of uterus	UBERON:0009853	93.63	gold quality
body of pancreas	UBERON:0001150	93.51	gold quality
ectocervix	UBERON:0012249	93.36	gold quality
right adrenal gland	UBERON:0001233	93.20	gold quality
thyroid gland	UBERON:0002046	93.16	gold quality
testis	UBERON:0000473	93.07	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
SMAD7

Upstream regulators (CollecTRI, top): KMT2B, SMARCA1

miRNA regulators (miRDB)

29 targeting PRMT5, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-7156-5P	99.64	68.81	1369
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-4273	99.45	67.93	1206
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-485-5P	99.10	64.78	1889
HSA-MIR-6884-5P	99.10	64.50	1987
HSA-MIR-4478	99.07	65.16	2320
HSA-MIR-376A-3P	99.06	69.17	1128
HSA-MIR-376B-3P	99.06	69.17	1128
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-2115-5P	98.66	68.07	1191
HSA-MIR-6754-5P	98.60	65.54	1627
HSA-MIR-4773	98.35	67.30	1710
HSA-MIR-3929	98.32	65.58	1026
HSA-MIR-4518	98.12	66.82	1030
HSA-MIR-6881-3P	98.04	68.24	1777
HSA-MIR-7113-5P	97.88	67.33	1735
HSA-MIR-1266-5P	97.71	66.92	1052
HSA-MIR-3173-5P	97.35	65.82	1282
HSA-MIR-6799-3P	97.35	65.60	1302
HSA-MIR-4690-3P	97.02	64.72	981
HSA-MIR-5685	97.02	64.34	1004
HSA-MIR-1233-3P	96.81	65.44	573
HSA-MIR-6856-3P	96.47	66.27	781
HSA-MIR-4268	94.45	64.09	819

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 94.9% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• Data show that PRMT5 can be found in association with hSWI/SNF complexes and is involved in regulating the expression of carbamoyl-phosphate synthase-aspartate carbamoyltransferase-dihydroorotase. (PMID:14559996)
• suppressor of tumorigenicity 7 (ST7) and nonmetastatic 23 (NM23) are direct targets of PRMT5-containing BRG1 and hBRM complexes (PMID:15485929)
• It was found that is the recruitment of methylarginine-specific protein(s) to cytokine promoter regions that regulates their gene expression. (PMID:15654770)
• found that FCP1 is a genuine substrate of PRMT5-methylation both in vivo and in vitro, and FCP1-associated PRMT5 can methylate histones H4 in vitro (PMID:15670829)
• Up-regulation of SKB1 is associated with gastric cancer (PMID:15701830)
• contrast to PRMT3, DAL-1/4.1B was found to mediate PRMT5 by either inhibiting (Sm proteins) or enhancing (myelin basic protein) protein methylation. (PMID:15737618)
• Lsm10 and Lsm11, which replace the Sm proteins D1 and D2 in the histone RNA processing U7 snRNPs, associate with pICln in vitro and in vivo without receiving sDMA modifications and with PRMT5 and SMN complexes (PMID:16087681)
• SUZ12 might have a role in transcriptional regulation through physical interaction with MEP50 that can be an adaptor between PRMT5 and its substrate H2A (PMID:16712789)
• results suggest distinct functions of the nuclear and the p44/protein arginine methyltransferase 5 complexes in the developing fetal testis and in the oncogenesis of testicular tumors. (PMID:17437848)
• aberrant expression of PRMT5 leads to altered epigenetic modification of chromatin, which in turn impacts transcriptional performance of anti-cancer genes and growth of transformed lymphoid cells (PMID:17627275)
• that in human cells, PRMT5 and PRMT7 are required for Sm protein sDMA modification, and that Sm protein symmetric dimethylarginine modification is required for snRNP biogenesis in human cells. (PMID:17709427)
• identification of the protein arginine methyltransferase 5 (PRMT5) as an effector recruited to SNAIL through an interaction with AJUBA that functions to repress the SNAIL target gene, E-cadherin (PMID:18347060)
• These results indicate that PRMT5 overexpression epigenetically alters the transcription of key tumor suppressor genes. (PMID:18694959)
• BLIMP1 and PRMT5 were expressed and arginine dimethylation of histones H2A and H4 was detected in human male gonocytes and intratubular germ cell neoplasia unclassified and most seminomas, while downregulated in embryonal carcinoma. (PMID:18992153)
• These results indicate that Ski complexes serve to maintain a TGF-beta-responsive promoter at a repressed basal level via the activities of histone deacetylase and histone arginine methyltransferase. (PMID:19032343)
• FGF-2 is a new substrate of PRMT5. (PMID:19086919)
• Loss of the H4 arginine 3 methylation mark through short hairpin RNA-mediated knockdown of PRMT5 leads to reduced DNMT3A binding, loss of DNA methylation and gene activation. (PMID:19234465)
• ZNF224 recruits the arginine methyltransferase PRMT5 on the transcriptional repressor complex of the aldolase A gene (PMID:19741270)
• The protein arginine methyltransferase 5 (PRMT5) localizes to the GA and forms complexes with several components involved in GA ribbon formation and vesicle tethering. (PMID:20421892)
• PRMT5 induces multiprotein repressor complex containing the histone modifying enzymes SUV4-20h1, casein kinase 2alpha in silencing fetal globin gene expression resulting in beta-thalassemia and sickle cell disease. (PMID:20495075)
• Increased PRMT5 activity mediates key events associated with cyclin D1-dependent neoplastic growth, including CUL4 repression, CDT1 overexpression, and DNA rereplication. (PMID:20951943)
• RioK1, a new interactor of protein arginine methyltransferase 5 (PRMT5), competes with pICln for binding and modulates PRMT5 complex composition and substrate specificity. (PMID:21081503)
• loss of Prmt5 function is early embryonic-lethal due to the abrogation of pluripotent cells in blastocysts (PMID:21159818)
• The activity of SHP is also increased by posttranslational methylation at Arg-57 by protein arginine methyltransferase 5 (PRMT5). (PMID:21262773)
• results indicate that phosphorylation of PRMT5 contributes to the mutant JAK2-induced myeloproliferative phenotype (PMID:21316606)
• COX2-dependent and independent activation of CK2alpha-Akt/uPA signal is mainly involved in urothelial carcinoma cell survival (PMID:21592330)
• results reveal a new cofactor for PDCD4 that alters its tumor suppressor functions and point to the utility of PDCD4/PRMT5 status as both a prognostic biomarker and a potential target for chemotherapy (PMID:21700716)
• Protein arginine methyltransferase 5 regulates ERK1/2 signal transduction amplitude and cell fate through CRAF. (PMID:21917714)
• The results not only provide insight into the molecular mechanisms by which PRMT5 contributes to growth control, but also justify therapeutic targeting of PRMT5. (PMID:21975038)
• analysis of structural insights into protein arginine symmetric dimethylation by PRMT5 (PMID:22143770)
• PRMT5 inhibits the PKCdelta- or 12-O-tetradecanoylphorbol-13-acetate-dependent increase in human involucrin expression, and PRMT5 dimethylates proteins in the p38delta complex. (PMID:22199349)
• Here the authors report that H3R2 is also symmetrically dimethylated (H3R2me2s) by PRMT5 and PRMT7 and present in euchromatic regions. (PMID:22231400)
• PRMT5 probably promotes tumor growth by stimulating cell proliferation and by participating in the construction of a tumor-favorable microenvironment via HIF-1 activation. (PMID:22266372)
• HOXA9 is required for TNF-alpha-dependent binding of PRMT5 to the E-selectin promoter in endothelial cells. (PMID:22269951)
• Data suggest that PRMT5 is highly expressed in lung cancer cells; PRMT5 expression is not detectable in benign lung tissues. Silencing PRMT5 expression strongly inhibits proliferation of lung adenocarcinoma cells in culture and in a xenograft model. (PMID:22708516)
• Protein arginine methyltransferase 5 is a potential oncoprotein that upregulates G1 cyclins/cyclin-dependent kinases and the phosphoinositide 3-kinase/AKT signaling cascade. (PMID:22726390)
• These results imply a novel mechanism by which PRMT5 controls cell growth and contributes to prostate tumorigenesis. (PMID:22952863)
• structure of the surprising hetero-octameric complex reveals the close interaction between the seven-bladed beta-propeller MEP50 and the N-terminal domain of PRMT5, and delineates the structural elements of substrate recognition. (PMID:23071334)
• type II protein arginine methyltransferase 5 has a role in the regulation of Circadian Per1 and CRY1 genes (PMID:23133559)
• PRMT5 triggers the symmetric dimethylation of EBNA2 RG domain to coordinate with EBNA2-mediated transcription. (PMID:23261437)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	prmt5	ENSDARG00000079605
mus_musculus	Prmt5	ENSMUSG00000023110
rattus_norvegicus	Prmt5	ENSRNOG00000012046
drosophila_melanogaster	csul	FBGN0015925
caenorhabditis_elegans		WBGENE00016408

Protein

Protein identifiers

Protein arginine N-methyltransferase 5 — O14744 (reviewed: O14744)

Alternative names: 72 kDa ICln-binding protein, Histone-arginine N-methyltransferase PRMT5, Jak-binding protein 1, Shk1 kinase-binding protein 1 homolog

All UniProt accessions (15): O14744, C9JSX3, G3V2F5, G3V2L6, G3V2X6, G3V3A3, G3V507, G3V580, G3V5L5, G3V5T6, H0YJ77, H0YJD3, H0YJX6, H0YJY6, H7BZ44

UniProt curated annotations — full annotation on UniProt →

Function. 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. 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. May methylate the N-terminal region of MBD2. 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 p53/TP53; methylation might possibly affect p53/TP53 target gene specificity. Involved in spliceosome maturation and mRNA splicing in prophase I spermatocytes through the catalysis of the symmetrical arginine dimethylation of SNRPB (small nuclear ribonucleoprotein-associated protein) and the interaction with tudor domain-containing protein TDRD6.

Subunit / interactions. Forms, at least, homodimers and homotetramers. Component of the methylosome complex, composed of PRMT5, WDR77 and CLNS1A. Found in a complex composed of PRMT5, WDR77 and RIOK1. RIOK1 and CLNS1A associate with PRMT5 in a mutually exclusive fashion, which allows the recruitment of distinct methylation substrates, such as nucleolin/NCL and Sm proteins, respectively. Interacts with PRDM1. Identified in a complex composed of methylosome and PRMT1 and ERH. Interacts with EGFR; methylates EGFR and stimulates EGFR-mediated ERK activation. Interacts with HOXA9. Interacts with SRGAP2. Found in a complex with COPRS, RUNX1 and CBFB. Interacts with CHTOP; the interaction symmetrically methylates CHTOP, but seems to require the presence of PRMT1. Interacts with EPB41L3; this modulates methylation of target proteins. Component of a high molecular weight E2F-pocket protein complex, CERC (cyclin E1 repressor complex). Associates with SWI/SNF remodeling complexes containing SMARCA2 and SMARCA4. Interacts with JAK2, SSTR1, SUPT5H, BRAF and with active RAF1. Interacts with LSM11, PRMT7 and SNRPD3. Interacts with COPRS; promoting its recruitment on histone H4. Interacts with CLNS1A/pICln. Identified in a complex with CLNS1A/pICln and Sm proteins. Interacts with RPS10. Interacts with WDR77. Interacts with IWS1. Interacts with CRY1. Interacts with POLR2A. Interacts with SMN1/SMN2. Interacts with LYAR; this interaction is direct. Interacts with TTC5/STRAP; this interaction is DNA damage-dependent and promotes PRMT5 interaction with p53/TP53. Interacts with p53/TP53 in response to DNA damage; the interaction is TTC5/STRAP dependent. Interacts with FAM47E; the interaction is direct, promotes PRMT5 localization to chromatin, and does not disrupt its association with WDR77 or STUB1. Interacts with TDRD6. Interacts with STUB1. Interacts with MBD2. Does not interact with MBD3.

Subcellular location. Cytoplasm. Nucleus. Chromosome. Golgi apparatus.

Tissue specificity. Ubiquitous.

Activity regulation. Activity is increased by EGF, HGF, FGF1 or FGF2 treatments, and slightly decreased by NGF treatment.

Similarity. Belongs to the class I-like SAM-binding methyltransferase superfamily. Protein arginine N-methyltransferase family.

Isoforms (5)

UniProt ID	Names	Canonical?
O14744-1	1	yes
O14744-2	2
O14744-4	4
O14744-5	5
O14744-3	3

RefSeq proteins (6): NP_001034708, NP_001269882, NP_001269883, NP_001269884, NP_001269885, NP_006100* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007857	Arg_MeTrfase_PRMT5	Family
IPR025799	Arg_MeTrfase	Family
IPR029063	SAM-dependent_MTases_sf	Homologous_superfamily
IPR035075	PRMT5	Domain
IPR035247	PRMT5_TIM	Domain
IPR035248	PRMT5_C	Domain

Pfam: PF05185, PF17285, PF17286

Enzyme classification (BRENDA):

• EC 2.1.1.320 — type II protein arginine methyltransferase (BRENDA: 10 organisms, 87 substrates, 243 inhibitors, 6 Km, 2 kcat entries)

Substrate kinetics (BRENDA)

3 substrates with measured Km, best-characterized 3. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
S-ADENOSYL-L-METHIONINE	—	3
[HISTONE H4 PEPTIDE]-L-ARGININE	0.0042–0.0102	2
[HISTONE H4(1-21)]-L-ARGININE	0.002	1

Catalyzed reactions (Rhea), 1 shown:

• L-arginyl-[protein] + 2 S-adenosyl-L-methionine = N(omega),N(omega)’-dimethyl-L-arginyl-[protein] + 2 S-adenosyl-L-homocysteine + 2 H(+) (RHEA:48108)

UniProt features (96 total): strand 33, helix 27, turn 9, binding site 7, sequence conflict 4, splice variant 3, region of interest 3, chain 2, mutagenesis site 2, active site 2, initiator methionine 1, site 1, modified residue 1, domain 1

Structure

Experimental structures (PDB)

90 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
9ZL3	X-RAY DIFFRACTION	1.71
9MGQ	X-RAY DIFFRACTION	1.85
6V0P	X-RAY DIFFRACTION	1.88
7ZVU	X-RAY DIFFRACTION	1.95
9ZL4	X-RAY DIFFRACTION	1.95
7ZUY	X-RAY DIFFRACTION	2
7S0U	X-RAY DIFFRACTION	2.01
7ZUP	X-RAY DIFFRACTION	2.01
7ZV2	X-RAY DIFFRACTION	2.01
8VEO	X-RAY DIFFRACTION	2.03
4GQB	X-RAY DIFFRACTION	2.06
9MGR	X-RAY DIFFRACTION	2.07
7ZUU	X-RAY DIFFRACTION	2.09
7S1R	X-RAY DIFFRACTION	2.1
6V0N	X-RAY DIFFRACTION	2.11
7SER	X-RAY DIFFRACTION	2.14
9EYV	X-RAY DIFFRACTION	2.15
9EYX	X-RAY DIFFRACTION	2.2
9PCA	X-RAY DIFFRACTION	2.2
7S1P	X-RAY DIFFRACTION	2.21
6RLL	X-RAY DIFFRACTION	2.22
9MGL	X-RAY DIFFRACTION	2.25
9MGM	X-RAY DIFFRACTION	2.25
9MRE	X-RAY DIFFRACTION	2.25
5EMJ	X-RAY DIFFRACTION	2.27
9EYW	X-RAY DIFFRACTION	2.3
5FA5	X-RAY DIFFRACTION	2.34
4X60	X-RAY DIFFRACTION	2.35
9EYU	X-RAY DIFFRACTION	2.35
5C9Z	X-RAY DIFFRACTION	2.36

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14744-F1	93.68	0.89

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (3): 327 (critical for specifying symmetric addition of methyl groups); 435 (proton donor/acceptor); 444 (proton donor/acceptor)

Ligand- & substrate-binding residues (7): 327; 333–334; 392; 419–420; 435; 444; 324

Post-translational modifications (1): 2

Mutagenesis-validated functional residues (2):

Position	Phenotype
365–369	increased mapk1/mapk3 phosphorylation in response to egf.
367–368	abolishes enzymatic activity.

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-191859	snRNP Assembly
R-HSA-3214858	RMTs methylate histone arginines
R-HSA-6804760	Regulation of TP53 Activity through Methylation
R-HSA-194441	Metabolism of non-coding RNA
R-HSA-212436	Generic Transcription Pathway
R-HSA-3247509	Chromatin modifying enzymes
R-HSA-3700989	Transcriptional Regulation by TP53
R-HSA-4839726	Chromatin organization
R-HSA-5633007	Regulation of TP53 Activity
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8953854	Metabolism of RNA

MSigDB gene sets: 340 (showing top): GOBP_CIRCADIAN_RHYTHM, PID_HDAC_CLASSI_PATHWAY, GOBP_RIBOSOME_BIOGENESIS, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_DNA_TEMPLATED_TRANSCRIPTION_TERMINATION, GOBP_REGULATION_OF_NUCLEAR_DIVISION, GOBP_POSITIVE_REGULATION_OF_RNA_SPLICING, NKX25_02, GOBP_POSITIVE_REGULATION_OF_MRNA_PROCESSING, GOBP_POSITIVE_REGULATION_OF_GLIAL_CELL_DIFFERENTIATION, GOBP_REGENERATION, GOBP_NEUROGENESIS, GOBP_CIRCADIAN_REGULATION_OF_GENE_EXPRESSION, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT

GO Biological Process (24): spliceosomal snRNP assembly (GO:0000387), chromatin remodeling (GO:0006338), DNA-templated transcription termination (GO:0006353), regulation of DNA-templated transcription (GO:0006355), regulation of mitotic nuclear division (GO:0007088), peptidyl-arginine methylation (GO:0018216), circadian regulation of gene expression (GO:0032922), peptidyl-arginine N-methylation (GO:0035246), endothelial cell activation (GO:0042118), negative regulation of gene expression via chromosomal CpG island methylation (GO:0044027), negative regulation of cell differentiation (GO:0045596), positive regulation of mRNA splicing, via spliceosome (GO:0048026), positive regulation of oligodendrocyte differentiation (GO:0048714), regulation of ERK1 and ERK2 cascade (GO:0070372), Golgi ribbon formation (GO:0090161), liver regeneration (GO:0097421), regulation of signal transduction by p53 class mediator (GO:1901796), positive regulation of adenylate cyclase-inhibiting dopamine receptor signaling pathway (GO:1904992), chromatin organization (GO:0006325), protein methylation (GO:0006479), regulation of gene expression (GO:0010468), methylation (GO:0032259), negative regulation of DNA-templated transcription (GO:0045892), rhythmic process (GO:0048511)

GO Molecular Function (18): p53 binding (GO:0002039), transcription corepressor activity (GO:0003714), methyltransferase activity (GO:0008168), methyl-CpG binding (GO:0008327), protein-arginine N-methyltransferase activity (GO:0016274), protein-arginine omega-N symmetric methyltransferase activity (GO:0035243), histone methyltransferase activity (GO:0042054), identical protein binding (GO:0042802), ribonucleoprotein complex binding (GO:0043021), histone H4R3 methyltransferase activity (GO:0044020), protein heterodimerization activity (GO:0046982), E-box binding (GO:0070888), histone H3 methyltransferase activity (GO:0140938), protein binding (GO:0005515), protein methyltransferase activity (GO:0008276), obsolete histone arginine N-methyltransferase activity (GO:0008469), transferase activity (GO:0016740), protein-containing complex binding (GO:0044877)

GO Cellular Component (10): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), cytosol (GO:0005829), methylosome (GO:0034709), histone methyltransferase complex (GO:0035097), chromosome (GO:0005694), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Metabolism of non-coding RNA	1
Chromatin modifying enzymes	1
Regulation of TP53 Activity	1
Metabolism of RNA	1
RNA Polymerase II Transcription	1
Chromatin organization	1
Generic Transcription Pathway	1
Transcriptional Regulation by TP53	1
Gene expression (Transcription)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytoplasm	3
mRNA splicing, via spliceosome	2
DNA-templated transcription	2
regulation of gene expression	2
protein binding	2
protein methyltransferase activity	2
protein-arginine N-methyltransferase activity	2
binding	2
intracellular membrane-bounded organelle	2
methyltransferase complex	2
protein-RNA complex assembly	1
chromatin organization	1
RNA biosynthetic process	1
regulation of RNA biosynthetic process	1
regulation of mitotic cell cycle	1
regulation of cell cycle process	1
regulation of nuclear division	1
mitotic nuclear division	1
protein methylation	1
peptidyl-arginine modification	1
circadian rhythm	1
peptidyl-arginine methylation	1
cell activation	1
negative regulation of gene expression, epigenetic	1
cell differentiation	1
regulation of cell differentiation	1
negative regulation of cellular process	1
negative regulation of developmental process	1
positive regulation of RNA splicing	1
regulation of mRNA splicing, via spliceosome	1
positive regulation of mRNA processing	1
positive regulation of glial cell differentiation	1
oligodendrocyte differentiation	1
regulation of oligodendrocyte differentiation	1
regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
Golgi organization	1
liver development	1
animal organ regeneration	1

Protein interactions and networks

STRING

3550 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PRMT5	WDR77	Q9BQA1	999
PRMT5	PRMT7	Q9NVM4	963
PRMT5	SNRPD3	P43331	939
PRMT5	CLNS1A	P54105	934
PRMT5	PRMT1	Q99873	927
PRMT5	COPRS	Q9NQ92	912
PRMT5	SMARCA4	P51532	909
PRMT5	PRMT3	O60678	892
PRMT5	TET1	Q8NFU7	886
PRMT5	TET3	O43151	882
PRMT5	PRDM4	Q9UKN5	861
PRMT5	PRMT6	Q96LA8	836
PRMT5	TET2	Q6N021	813
PRMT5	PRMT8	Q9NR22	811
PRMT5	SUZ12	Q15022	809

IntAct

369 interactions, top by confidence:

A	B	Type	Score
PRMT5	WDR77	psi-mi:“MI:0915”(physical association)	0.960
WDR77	PRMT5	psi-mi:“MI:0407”(direct interaction)	0.960
PRMT5	WDR77	psi-mi:“MI:0407”(direct interaction)	0.960
WDR77	PRMT5	psi-mi:“MI:0915”(physical association)	0.960
WDR77	PRMT5	psi-mi:“MI:0914”(association)	0.960
PRMT5	CLNS1A	psi-mi:“MI:0914”(association)	0.830
CLNS1A	PRMT5	psi-mi:“MI:0914”(association)	0.830
CLNS1A	PRMT5	psi-mi:“MI:0407”(direct interaction)	0.830
H4C16	PRMT5	psi-mi:“MI:0213”(methylation reaction)	0.760
PRMT5	H4C16	psi-mi:“MI:0915”(physical association)	0.760
RIOK1	PRMT5	psi-mi:“MI:0914”(association)	0.710
PRMT5	RIOK1	psi-mi:“MI:0915”(physical association)	0.710
RIOK1	PRMT5	psi-mi:“MI:0915”(physical association)	0.710
PRMT5	PRMT5	psi-mi:“MI:0914”(association)	0.690
PRMT5	PRMT5	psi-mi:“MI:0407”(direct interaction)	0.690
PRMT5	SNRPB	psi-mi:“MI:0915”(physical association)	0.670
GRB2	PRMT5	psi-mi:“MI:0915”(physical association)	0.670
IFT88	IFT56	psi-mi:“MI:0914”(association)	0.640
POLR2C	SUPT5H	psi-mi:“MI:0914”(association)	0.640
Ajuba	PRMT5	psi-mi:“MI:0915”(physical association)	0.620
Ajuba	PRMT5	psi-mi:“MI:0914”(association)	0.620
Ajuba	PRMT5	psi-mi:“MI:0407”(direct interaction)	0.620

BioGRID (805): PRMT5 (Affinity Capture-MS), PRMT5 (Two-hybrid), PRMT5 (Two-hybrid), PRMT5 (Affinity Capture-MS), PRMT5 (Affinity Capture-MS), PRMT5 (Affinity Capture-MS), PRMT5 (Affinity Capture-MS), PRMT5 (Affinity Capture-MS), PRMT5 (Affinity Capture-MS), PRMT5 (Affinity Capture-MS), CTPS1 (Co-fractionation), DYNC1H1 (Co-fractionation), EIF2S1 (Co-fractionation), NCBP1 (Co-fractionation), NSFL1C (Co-fractionation)

ESM2 similar proteins: A2APY7, A3KP37, A7YW45, B2GV71, M1BYJ7, O08691, O08701, O14744, O46504, O80543, P20373, P41819, P49900, P78540, P78697, Q1JPL4, Q2LZ79, Q337B8, Q3KRD0, Q4G064, Q4R5M3, Q4V7R3, Q58DL1, Q5R698, Q5RBS1, Q5TEU4, Q66KM2, Q66L51, Q6AY46, Q6BSY5, Q6C7H6, Q6FKY3, Q6NUA1, Q6NYF0, Q6PI48, Q6YXZ7, Q75C90, Q7SYK1, Q7T0W5, Q80XC2

Diamond homologs: A2X0Q3, A2Y953, A2YPT7, A7YW45, B3DLB3, O14744, P46580, P78963, Q4R5M3, Q54KI3, Q5R698, Q6NUA1, Q6NZB1, Q6YXZ7, Q7XI75, Q8CIG8, Q8GWT4, Q9MAT5, Q9R144, Q9SNQ2, Q9U6Y9, A0A3Q0KHE7, A0JMU5, A2XYY8, A2Z0C0, A2Z8S0, A3KPF2, A4IR29, A4J7F1, A6TSL8, A8IEF3, A8MG53, B0JX03, B0JYW5, B0W3L6, B3M1E1, B3MF31, B3NP10, B3P4N5, B4GZ20

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
JAK2	down-regulates	PRMT5	phosphorylation
PRMT5	“up-regulates activity”	HOXA9	methylation
SRC	“down-regulates activity”	PRMT5	phosphorylation
STK11	“up-regulates activity”	PRMT5	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 115 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
TP53 Regulates Transcription of DNA Repair Genes	6	12.8×	1e-03
snRNP Assembly	5	12.4×	4e-03
Signaling by NOTCH	5	10.3×	5e-03
Transcription of the HIV genome	5	10.2×	5e-03
RNA Polymerase II Pre-transcription Events	6	9.7×	3e-03
ESR-mediated signaling	6	9.1×	4e-03
Signaling by ALK fusions and activated point mutants	5	8.8×	8e-03
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	5	8.6×	9e-03

GO biological processes:

GO term	Partners	Fold	FDR
spliceosomal snRNP assembly	5	29.1×	7e-04
RNA splicing	8	7.1×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

57 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	32
Likely benign	3
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

1982 predictions. Top by Δscore:

Variant	Effect	Δscore
14:22921052:GGCTG:G	acceptor_gain	1.0000
14:22921054:CTG:C	acceptor_gain	1.0000
14:22921055:TG:T	acceptor_gain	1.0000
14:22921057:C:CC	acceptor_gain	1.0000
14:22922435:ACACT:A	donor_loss	1.0000
14:22922436:CACTC:C	donor_loss	1.0000
14:22922437:ACTC:A	donor_loss	1.0000
14:22922438:CTCAC:C	donor_loss	1.0000
14:22922439:TCA:T	donor_loss	1.0000
14:22922440:CACTC:C	donor_loss	1.0000
14:22922441:A:AC	donor_gain	1.0000
14:22922441:A:C	donor_loss	1.0000
14:22922441:ACT:A	donor_gain	1.0000
14:22922442:C:CA	donor_gain	1.0000
14:22922442:CT:C	donor_gain	1.0000
14:22922442:CTC:C	donor_gain	1.0000
14:22922442:CTCA:C	donor_gain	1.0000
14:22922442:CTCAG:C	donor_gain	1.0000
14:22922454:T:TA	donor_gain	1.0000
14:22922737:CCTA:C	donor_loss	1.0000
14:22922738:CTAC:C	donor_loss	1.0000
14:22922740:A:AC	donor_gain	1.0000
14:22922741:C:CC	donor_gain	1.0000
14:22922741:CCT:C	donor_gain	1.0000
14:22922831:TGGGC:T	acceptor_gain	1.0000
14:22922832:GGGC:G	acceptor_gain	1.0000
14:22922833:GGC:G	acceptor_gain	1.0000
14:22922834:GC:G	acceptor_gain	1.0000
14:22922834:GCCTG:G	acceptor_loss	1.0000
14:22922835:CC:C	acceptor_gain	1.0000

AlphaMissense

4190 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:22920929:C:A	G630V	1.000
14:22920929:C:T	G630D	1.000
14:22920937:G:C	N627K	1.000
14:22920937:G:T	N627K	1.000
14:22920973:C:A	W615C	1.000
14:22920973:C:G	W615C	1.000
14:22920975:A:G	W615R	1.000
14:22920975:A:T	W615R	1.000
14:22922197:A:C	F580L	1.000
14:22922197:A:T	F580L	1.000
14:22922198:A:C	F580C	1.000
14:22922198:A:G	F580S	1.000
14:22922199:A:C	F580V	1.000
14:22922199:A:G	F580L	1.000
14:22922200:C:A	W579C	1.000
14:22922200:C:G	W579C	1.000
14:22922202:A:G	W579R	1.000
14:22922202:A:T	W579R	1.000
14:22922474:A:C	F555L	1.000
14:22922474:A:T	F555L	1.000
14:22922476:A:G	F555L	1.000
14:22922481:C:T	G553D	1.000
14:22922490:C:T	G550D	1.000
14:22922813:A:T	V503E	1.000
14:22924034:A:G	L450P	1.000
14:22924038:A:G	C449R	1.000
14:22924043:G:T	P447H	1.000
14:22924049:A:C	L445W	1.000
14:22924051:T:A	E444D	1.000
14:22924051:T:G	E444D	1.000

dbSNP variants (sampled 300 via entrez): RS1000364140 (14:22928873 C>G), RS1000947209 (14:22920194 A>G), RS1001102865 (14:22929762 C>A,G,T), RS1001244882 (14:22921781 C>T), RS1001981358 (14:22923356 A>G,T), RS1002117219 (14:22923765 A>C), RS1002921660 (14:22923532 G>A), RS1002967777 (14:22930029 T>G), RS1003161018 (14:22931155 G>A,C), RS1003319406 (14:22930660 T>G), RS1003706218 (14:22925450 C>A), RS1003718276 (14:22925762 G>A), RS1004205900 (14:22925696 T>C), RS1004609669 (14:22926593 T>A), RS1005341842 (14:22927063 G>A)

Disease associations

OMIM: gene MIM:604045 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST006135_13	Cortical amyloid beta load	6.000000e-06
GCST006135_3	Cortical amyloid beta load	5.000000e-06
GCST006135_4	Cortical amyloid beta load	4.000000e-07
GCST006135_6	Cortical amyloid beta load	4.000000e-06
GCST009723_26	Vertical cup-disc ratio (adjusted for vertical disc diameter)	1.000000e-13

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007707	cerebral amyloid deposition measurement
EFO:0006939	cup-to-disc ratio measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL1795116 (SINGLE PROTEIN), CHEMBL3137261 (PROTEIN COMPLEX), CHEMBL4748215 (PROTEIN-PROTEIN INTERACTION), CHEMBL5483002 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

5 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 5,310 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1088977	ADEMETIONINE	3	1,522
CHEMBL1214186	SINEFUNGIN	2	2,165
CHEMBL142304	STILBAMIDINE	2	889
CHEMBL4466233	PEMRAMETOSTAT	2	542
CHEMBL4249337	ONAMETOSTAT	1	192

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — 2.1.1.- Protein arginine N-methyltransferases

Most potent curated ligand interactions (10 total), top 10:

Ligand	Action	Affinity	Parameter
onametostat	Inhibition	9.2	pKd
ralometostat	Binding	8.72	pKd
EPZ015666	Inhibition	8.3	pKi
AZ-PRMT5i-1	Inhibition	8.26	pIC50
GSK591	Inhibition	7.96	pIC50
navlimetostat	Inhibition	7.92	pIC50
LLY-283	Inhibition	7.7	pIC50
PRMT5 inhibitor D3	Inhibition	7.68	pIC50
pemrametostat	Inhibition	7.33	pIC50
DS-437	Inhibition	5.23	pIC50

Binding affinities (BindingDB)

1065 measured of 2091 human assays (2091 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(2S,3S,4R,5R)-2-[(1R)-1-(3,4-dichlorocyclohexa-2,4-dien-1-yl)-1-hydroxyethyl]-5-[(4E)-4-hydroxyimino-4aH-pyrrolo[2,3-d]pyrimidin-7-yl]oxolane-3,4-diol	IC50	0.2 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
(1S,2R,3S,5R)-3-[2-(2-amino-3-chloroquinolin-7-yl)ethyl]-5-[(4Z)-4-methoxyimino-4aH-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentane-1,2-diol	IC50	0.2 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
(2R,3S,4R,5R)-2-[(R)-(3,4-dichlorophenyl)-hydroxymethyl]-5-[4-(2-methylhydrazinyl)-1,2,4a,7a-tetrahydropyrrolo[2,3-d]pyrimidin-7-yl]oxolane-3,4-diol	IC50	0.3 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
(1S,2R,3S,5R)-3-[2-[2-(cyclopropylmethylamino)quinolin-7-yl]ethyl]-5-[(4Z)-4-hydroxyimino-4aH-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentane-1,2-diol	IC50	0.33 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
6-(5,8-dioxa-2-azatricyclo[4.3.0.03,7]nonane-2-carbonyl)-2-[(2R)-2-hydroxy-2-[(3S)-1,2,3,4-tetrahydroisoquinolin-3-yl]ethyl]-4,4-dimethyl-3H-isoquinolin-1-one	IC50	0.35 nM	US-11098059
(2R,3S,4R,5R)-2-[(R)-(3,4-dichlorophenyl)-hydroxymethyl]-5-[4-(hydroxyamino)-1,2,4a,7a-tetrahydropyrrolo[2,3-d]pyrimidin-7-yl]oxolane-3,4-diol	IC50	0.4 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
2-[(2R)-2-hydroxy-2-[(3S)-1,2,3,4-tetrahydroisoquinolin-3-yl]ethyl]-6-[(1R,5S)-3-methoxy-8-azabicyclo[3.2.1]octane-8-carbonyl]-4,4-dimethyl-3H-isoquinolin-1-one	IC50	0.44 nM	US-11098059
2-[(2R)-2-hydroxy-2-[(3S)-1,2,3,4-tetrahydroisoquinolin-3-yl]ethyl]-6-[(1R,5S)-3-methoxy-8-azabicyclo[3.2.1]octane-8-carbonyl]-4,4-dimethyl-3H-isoquinolin-1-one	IC50	0.5 nM	US-11098059
6-[(1R,5S)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-[(2R)-2-hydroxy-2-[(3S)-1,2,3,4-tetrahydroisoquinolin-3-yl]ethyl]-4,4-dimethyl-3H-isoquinolin-1-one	IC50	0.52 nM	US-11098059
US11220524, Example 20	IC50	0.6 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
(2R,3S,4R,5R)-2-[(R)-(3,4-difluorophenyl)-hydroxymethyl]-5-[4-(hydroxyamino)-1,2,4a,7a-tetrahydropyrrolo[2,3-d]pyrimidin-7-yl]oxolane-3,4-diol	IC50	0.6 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
(1S,2R,3S,5R)-3-[2-(2-aminoquinolin-7-yl)ethyl]-5-[(4Z)-4-methoxyimino-4aH-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentane-1,2-diol	IC50	0.64 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
US11220524, Example 63	IC50	0.7 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
US11220524, Example 80	IC50	0.7 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
(1S,2R,3S,5R)-3-[2-[2-(cyclopropylmethylamino)quinolin-7-yl]ethyl]-5-[(4Z)-4-methoxyimino-4aH-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentane-1,2-diol	IC50	0.82 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
(2R,3S,4R,5R)-2-[(R)-(3,4-dichlorophenyl)-hydroxymethyl]-5-[4-(methoxyamino)-1,2,4a,7a-tetrahydropyrrolo[2,3-d]pyrimidin-7-yl]oxolane-3,4-diol	IC50	1.8 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
US11220524, Example 65	IC50	1.9 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
(1S,2S,3R,5S)-3-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-5-[(6-pyrazolidin-4-yl-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy]cyclopentane-1,2-diol	IC50	2 nM	US-10709709: Substituted carbonucleoside derivatives useful as anticancer agents
US11220524, Example 93-B	IC50	2.3 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
US11220524, Example 37	IC50	2.4 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
US11220524, Example 99	IC50	2.4 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
(2S,3S,4R,5R)-2-[(1R)-1-(3,4-dichlorophenyl)-1-hydroxyethyl]-5-[4-(methoxyamino)-1,2,4a,7a-tetrahydropyrrolo[2,3-d]pyrimidin-7-yl]oxolane-3,4-diol	IC50	2.6 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
(2R,3R,4S,5R)-2-(4-hydrazinyl-1,2,4a,7a-tetrahydropyrrolo[2,3-d]pyrimidin-7-yl)-5-[(R)-hydroxy-[4-(trifluoromethyl)phenyl]methyl]oxolane-3,4-diol	IC50	2.7 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
(1R,2S,3R,5S)-3-[(4Z)-4-methoxyimino-4aH-pyrrolo[2,3-d]pyrimidin-7-yl]-5-[2-[2-(methylamino)quinolin-7-yl]ethyl]cyclopentane-1,2-diol	IC50	2.7 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
(2S,3S,4R,5R)-2-[(1R)-1-(4-chlorophenyl)-1-hydroxyethyl]-5-[4-(hydroxyamino)-1,2,4a,7a-tetrahydropyrrolo[2,3-d]pyrimidin-7-yl]oxolane-3,4-diol	IC50	2.8 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
US11220524, Example 72	IC50	2.8 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
(1S,2S,3S,5R)-3-[[5-fluoro-6-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]oxy]-5-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol	IC50	3 nM	US-10709709: Substituted carbonucleoside derivatives useful as anticancer agents
US11220524, Example 78	IC50	3.1 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
(1S,2R,3S,5R)-3-[2-[2-(cyclopropylmethylamino)quinolin-7-yl]ethyl]-5-[(4Z)-4-(methylhydrazinylidene)-4aH-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentane-1,2-diol	IC50	3.2 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
(1S,2R,3S,5R)-3-[(1S)-1-(3,4-dichlorophenyl)-1-hydroxyethyl]-5-[4-(hydroxyamino)-1,2,4a,7a-tetrahydropyrrolo[2,3-d]pyrimidin-7-yl]cyclopentane-1,2-diol	IC50	3.4 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
(2R,3S,4R,5R)-2-[(R)-(3,4-dichlorophenyl)-hydroxymethyl]-5-[4-(ethoxyamino)-1,2,4a,7a-tetrahydropyrrolo[2,3-d]pyrimidin-7-yl]oxolane-3,4-diol	IC50	3.9 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
4-(aminomethyl)-6-[5-[hydroxy(phenyl)methyl]-3-pyridinyl]-3,4,4a,5,6,7,8,8a-octahydro-2H-phthalazin-1-one	IC50	5.8 nM	US-11479551: MTA-cooperative PRMT5 inhibitors
US11220524, Example 37-B	IC50	6.3 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
(2R,3S,4R,5R)-2-[(R)-(4-chlorophenyl)-hydroxymethyl]-5-[4-(2-methylhydrazinyl)-1,2,4a,7a-tetrahydropyrrolo[2,3-d]pyrimidin-7-yl]oxolane-3,4-diol	IC50	8.3 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
(2R,3S,4R,5R)-2-[(R)-hydroxy-[3-methyl-4-(trifluoromethyl)phenyl]methyl]-5-[4-(methoxyamino)-1,2,4a,7a-tetrahydropyrrolo[2,3-d]pyrimidin-7-yl]oxolane-3,4-diol	IC50	8.4 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
US11220524, Example 62	IC50	8.6 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
(2S,3S,4R,5R)-2-[(1R)-1-(3,4-dichlorophenyl)-1-hydroxyethyl]-5-[4-(hydroxyamino)-1,2,4a,7a-tetrahydropyrrolo[2,3-d]pyrimidin-7-yl]oxolane-3,4-diol	IC50	9.6 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
US11220524, Example 73	IC50	9.7 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
(S)-6-((1-acetylpiperidin-4-yl)amino)-N-(2-hydroxy-3-(1,3,4,9-tetrahydro-2H-pyrido [3,4-b]indol-2-yl)propyl)pyrimidine-4-carboxamide	IC50	10 nM	US-11274098: Tricyclic compounds for use in treatment of proliferative disorders
(2R,3S,4R,5R)-2-[(R)-(3,4-difluorophenyl)-hydroxymethyl]-5-[4-(methoxyamino)-1,2,4a,7a-tetrahydropyrrolo[2,3-d]pyrimidin-7-yl]oxolane-3,4-diol	IC50	10.2 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
(2R,3S,4R,5R)-2-[(R)-(3,4-dichlorophenyl)-hydroxymethyl]-5-[5-ethynyl-4-(methoxyamino)-1,2,4a,7a-tetrahydropyrrolo[2,3-d]pyrimidin-7-yl]oxolane-3,4-diol	IC50	10.2 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
2-[(2S)-2-hydroxy-2-[(3S)-1,2,3,4-tetrahydroisoquinolin-3-yl]ethyl]-6-[(1R,5S)-3-methoxy-8-azabicyclo[3.2.1]octane-8-carbonyl]-4,4-dimethyl-3H-isoquinolin-1-one	IC50	11.3 nM	US-11098059
US11220524, Example 50-B	IC50	11.7 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
CHEMBL4634826	EC50	12 nM
4-(aminomethyl)-6-[5-(benzenesulfinyl)-3-pyridinyl]-3,4,4a,5,6,7,8,8a-octahydro-2H-phthalazin-1-one	IC50	12 nM	US-11479551: MTA-cooperative PRMT5 inhibitors
(2R,3S,4R,5R)-2-[(R)-(4-chlorophenyl)-hydroxymethyl]-5-[4-(hydroxyamino)-2-methyl-1,2,4a,7a-tetrahydropyrrolo[2,3-d]pyrimidin-7-yl]oxolane-3,4-diol	IC50	13.9 nM	US-11220524: Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
(1S,2S,3R,5S)-3-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-5-[[6-(1H-pyrazol-5-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]oxy]cyclopentane-1,2-diol	IC50	14 nM	US-10709709: Substituted carbonucleoside derivatives useful as anticancer agents
N-[(2S)-3-(2,3-dihydro-1H-inden-2-ylamino)-2-hydroxypropyl]-2-ethoxy-4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)benzamide	IC50	15 nM	US-10005792: Aminoindane-, aminotetrahydronaphthalene- and aminobenzocyclobutane-derived PRMT5-inhibitors
2-ethoxy-N-[(2R)-2-[(3S)-7-methoxy-1,2,3,4-tetrahydroisoquinolin-3-yl]propyl]-4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)benzamide	IC50	15 nM	US-10421743: Tetrahydroisoquinolines as PRMT5 inhibitors
N-[(2R)-2-[(3S)-7-methoxy-1,2,3,4-tetrahydroisoquinolin-3-yl]propyl]-4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)benzamide	IC50	18 nM	US-10421743: Tetrahydroisoquinolines as PRMT5 inhibitors

ChEMBL bioactivities

4903 potent at pChembl≥5 of 5224 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.94	Kd	0.0114	nM	CHEMBL4563402
10.70	Ki	0.02	nM	CHEMBL4441584
10.70	Ki	0.02	nM	CHEMBL5180177
10.30	Ki	0.05	nM	CHEMBL5426836
10.30	Ki	0.05	nM	CHEMBL4872234
10.00	Ki	0.1	nM	CHEMBL6163998
10.00	Ki	0.1	nM	CHEMBL6166947
10.00	Ki	0.1	nM	CHEMBL6143724
10.00	Ki	0.1	nM	CHEMBL6143495
10.00	Ki	0.1	nM	CHEMBL6148651
9.89	IC50	0.13	nM	ONAMETOSTAT
9.89	IC50	0.13	nM	CHEMBL5203719
9.85	IC50	0.14	nM	ONAMETOSTAT
9.80	IC50	0.16	nM	CHEMBL4564327
9.80	IC50	0.16	nM	CHEMBL4541714
9.70	IC50	0.2	nM	CHEMBL5865819
9.70	IC50	0.2	nM	CHEMBL5796835
9.70	Ki	0.2	nM	CHEMBL6145605
9.70	Ki	0.2	nM	CHEMBL6168533
9.68	IC50	0.21	nM	CHEMBL5757382
9.62	Kd	0.241	nM	CHEMBL4441584
9.62	IC50	0.24	nM	CHEMBL5790903
9.60	IC50	0.25	nM	CHEMBL4541714
9.60	IC50	0.25	nM	ONAMETOSTAT
9.54	IC50	0.29	nM	CHEMBL5747648
9.52	IC50	0.3	nM	CHEMBL5861732
9.51	IC50	0.31	nM	CHEMBL5810961
9.49	IC50	0.32	nM	CHEMBL4577464
9.48	IC50	0.33	nM	CHEMBL5894143
9.46	IC50	0.35	nM	CHEMBL5863900
9.44	IC50	0.36	nM	CHEMBL5774632
9.40	IC50	0.4	nM	CHEMBL4454890
9.40	IC50	0.4	nM	CHEMBL4543007
9.40	IC50	0.4	nM	CHEMBL5187591
9.40	IC50	0.4	nM	CHEMBL5973136
9.40	IC50	0.4	nM	CHEMBL5761913
9.40	IC50	0.4	nM	CHEMBL6103457
9.40	Ki	0.4	nM	CHEMBL6133844
9.38	IC50	0.42	nM	CHEMBL5283866
9.38	IC50	0.42	nM	CHEMBL5559161
9.38	IC50	0.42	nM	CHEMBL5560909
9.38	IC50	0.42	nM	CHEMBL5613744
9.38	IC50	0.42	nM	CHEMBL6176251
9.36	IC50	0.44	nM	CHEMBL5755426
9.33	IC50	0.47	nM	CHEMBL6055014
9.30	IC50	0.5	nM	CHEMBL6007359
9.30	IC50	0.5	nM	CHEMBL5945691
9.30	IC50	0.5	nM	CHEMBL5076664
9.30	IC50	0.5	nM	CHEMBL5789744
9.30	IC50	0.5	nM	CHEMBL5965955

PubChem BioAssay actives

760 with measured affinity, of 1525 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2R,3R,4S,5R)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(R)-(4-chloro-3-fluorophenyl)-hydroxymethyl]oxolane-3,4-diol	1593837: Inhibition of PRMT5 (unknown origin)	ki	<0.0001	uM
(1S,2S,3S,5R)-3-[[6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl]oxy]-5-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol	1997206: Binding affinity to N-terminal 6xHis-tagged full length human PRMT5/MEP50 expressed in sf21 cells using S-Adenosyl-L-methionine as substrate assessed as dissociation constant incubated for 25 to 60 mins by liquid scintillation analysis	kd	<0.0001	uM
2-[4-[4-(aminomethyl)-1-oxo-2H-phthalazin-6-yl]-1-methylpyrazol-5-yl]-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile	1825252: Binding affinity to human PRMT5 assessed as dissociation constant in presence of MTA by SPR analysis	kd	<0.0001	uM
(2S,3S,4R,5S)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(R)-(4-chloro-3-fluorophenyl)-hydroxymethyl]oxolane-3,4-diol	1882380: Binding affinity to PRMT5 (unknown origin) assessed as inhibition constant	ki	<0.0001	uM
(1S,2R,3S,5R)-3-[2-(2-amino-3-bromoquinolin-7-yl)ethyl]-5-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol	1530643: Inhibition of full-length human N-terminal FLAG-tagged PRMT5 expressed in Sf9 insect cells using histone H2A as peptide after 120 mins in presence of SAM by high throughput mass spectrometer assay	ic50	0.0001	uM
(1R,2S,3R,5S)-3-[2-(2-amino-3-bromoquinolin-7-yl)ethyl]-5-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol	1882374: Inhibition of PRMT5 (unknown origin)	ic50	0.0001	uM
2-amino-3-methyl-N-[(4R)-4,5,6,7-tetrahydro-1H-indazol-4-yl]-N-[[5-(trifluoromethyl)-2-pyridinyl]methyl]quinoline-6-carboxamide	1997247: Binding affinity to PRMT5/MEP50 (unknown origin) using histone H4 peptide assessed as inhibition constant preincubated for 24 hrs followed by substrate addition and measured for 2 hrs in the presence of SAM by MTase-Glo Methyl Transferase Assay	ki	0.0001	uM
(1R,2S,3R,5S)-3-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[2-(2-aminoquinolin-7-yl)ethyl]cyclopentane-1,2-diol	1593845: Inhibition of PRMT5 in human A549 cells assessed as reduction in sDMA production after 48 hrs by Hoechst Stain/HCS CellMask Deep Red Stain based immunohistochemistry method	ic50	0.0002	uM
(1R,2S,3R,5S)-3-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[2-(6-chloro-3-methylimidazo[1,2-a]pyridin-7-yl)ethyl]cyclopentane-1,2-diol	1593844: Inhibition of full-length human N-terminal FLAG-tagged PRMT5/full length N-terminal His6-tagged MEP50 (unknown origin) expressed in baculovirus infected Sf9 insect cells assessed as reduction of S-adenosyl-L-homocysteine formation using human recombinant histone H2A (1 to 130 residues) as substrate after 1 hr in the presence of S-adenosyl-L-methionine by high throughput mass spectrometry	ic50	0.0002	uM
(1R,2S,3R,5S)-3-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[2-(2,3-dimethylimidazo[1,2-a]pyridin-7-yl)ethyl]cyclopentane-1,2-diol	1593844: Inhibition of full-length human N-terminal FLAG-tagged PRMT5/full length N-terminal His6-tagged MEP50 (unknown origin) expressed in baculovirus infected Sf9 insect cells assessed as reduction of S-adenosyl-L-homocysteine formation using human recombinant histone H2A (1 to 130 residues) as substrate after 1 hr in the presence of S-adenosyl-L-methionine by high throughput mass spectrometry	ic50	0.0002	uM
methyl 2-[[2-[(6-methoxy-1H-benzimidazol-2-yl)sulfanyl]acetyl]amino]benzoate	1882374: Inhibition of PRMT5 (unknown origin)	ic50	0.0003	uM
(1R,2S,3R,5S)-3-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[2-(6-fluoro-3-methylimidazo[1,2-a]pyridin-7-yl)ethyl]cyclopentane-1,2-diol	1593844: Inhibition of full-length human N-terminal FLAG-tagged PRMT5/full length N-terminal His6-tagged MEP50 (unknown origin) expressed in baculovirus infected Sf9 insect cells assessed as reduction of S-adenosyl-L-homocysteine formation using human recombinant histone H2A (1 to 130 residues) as substrate after 1 hr in the presence of S-adenosyl-L-methionine by high throughput mass spectrometry	ic50	0.0003	uM
(1R,2S,3R,5S)-3-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[2-[2-(cyclopropylmethylamino)quinolin-7-yl]ethyl]cyclopentane-1,2-diol	1593845: Inhibition of PRMT5 in human A549 cells assessed as reduction in sDMA production after 48 hrs by Hoechst Stain/HCS CellMask Deep Red Stain based immunohistochemistry method	ic50	0.0004	uM
(1S,2R,3S,5R)-3-[4-(6-amino-2-pyridinyl)butyl]-5-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol	1593844: Inhibition of full-length human N-terminal FLAG-tagged PRMT5/full length N-terminal His6-tagged MEP50 (unknown origin) expressed in baculovirus infected Sf9 insect cells assessed as reduction of S-adenosyl-L-homocysteine formation using human recombinant histone H2A (1 to 130 residues) as substrate after 1 hr in the presence of S-adenosyl-L-methionine by high throughput mass spectrometry	ic50	0.0004	uM
(1R,2S,3R,5S)-3-[3-(6-amino-2-pyridinyl)propyl]-5-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol	1882374: Inhibition of PRMT5 (unknown origin)	ic50	0.0004	uM
(2S)-2-amino-N-[2-[[(2R)-1-amino-4-[[amino-[2-[[(2S,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methylsulfanyl]ethylamino]methylidene]amino]-1-oxobutan-2-yl]amino]-2-oxoethyl]-5-(diaminomethylideneamino)pentanamide	1946282: Inhibition of human PRMT5 by fluorescence-based SAHH-coupled assay	ic50	0.0004	uM
(2S)-5-amino-N-[(2R)-1-amino-5-[[N’-[3-[[(2S,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methylsulfanyl]propyl]carbamimidoyl]amino]-1-oxopentan-2-yl]-2-[[2-[[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]acetyl]amino]pentanamide	2073632: Inhibition of PRMT5 (unknown origin) by HotSpot profiling analysis	ic50	0.0004	uM
(2S)-2-amino-N-[2-[[(2S)-1-amino-4-[[N’-[3-[[(2S,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methylsulfanyl]propyl]carbamimidoyl]amino]-1-oxobutan-2-yl]amino]-2-oxoethyl]-5-(diaminomethylideneamino)pentanamide	2074356: Inhibition of PRMT5 (unknown origin)	ic50	0.0004	uM
(2S)-2-[[(2S)-5-amino-2-[[2-[[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]acetyl]amino]pentanoyl]amino]-5-[[N’-[3-[[(2S,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methylsulfanyl]propyl]carbamimidoyl]amino]pentanoic acid	2127549: Inhibition of human PRMT5/MEP50 using Histone H2 as substrate and SAM as cofactor by radiometric HotSpot assay	ic50	0.0004	uM
(2R,3R,3aS,6S,6aR)-6-[(2-amino-3-bromoquinolin-7-yl)methyl]-2-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-2,3,4,5,6,6a-hexahydrocyclopenta[b]furan-3,3a-diol	1749891: Inhibition of PRMT5 (unknown origin) assessed as inhibition of symmetric dimethylation of arginine incubated for 3 days by fluorescence based cellular target engagement assay	ec50	0.0005	uM
(2R,3S,4R,5R)-2-[(R)-(4-chlorophenyl)-hydroxymethyl]-5-(4-hydrazinylpyrrolo[2,3-d]pyrimidin-7-yl)oxolane-3,4-diol	1593838: Inhibition of PRMT5 (unknown origin)/MEP50 (unknown origin) using histone H2 as substrate preincubated for 15 to 20 mins followed by S-[methyl-3H]adenosyl-L-methionine addition measured after 60 mins by liquid scintillation counting	ic50	0.0006	uM
(1S,2R,3aR,4S,6aR)-2-(4-amino-5-fluoropyrrolo[2,3-d]pyrimidin-7-yl)-4-[(2-amino-3-fluoroquinolin-7-yl)methyl]-2,3,3a,4,5,6-hexahydro-1H-pentalene-1,6a-diol	1749891: Inhibition of PRMT5 (unknown origin) assessed as inhibition of symmetric dimethylation of arginine incubated for 3 days by fluorescence based cellular target engagement assay	ec50	0.0007	uM
(1R,2S,3R,5S)-3-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[2-(3-methylimidazo[1,2-a]pyridin-7-yl)ethyl]cyclopentane-1,2-diol	1593844: Inhibition of full-length human N-terminal FLAG-tagged PRMT5/full length N-terminal His6-tagged MEP50 (unknown origin) expressed in baculovirus infected Sf9 insect cells assessed as reduction of S-adenosyl-L-homocysteine formation using human recombinant histone H2A (1 to 130 residues) as substrate after 1 hr in the presence of S-adenosyl-L-methionine by high throughput mass spectrometry	ic50	0.0008	uM
(2R,3R,3aS,6S,6aR)-6-[(2-amino-3-bromoquinolin-7-yl)methyl]-2-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-3,4,6,6a-tetrahydro-2H-furo[3,4-b]furan-3,3a-diol	2106926: Inhibition of PRMT5/MEP50 (unknown origin)	ic50	0.0008	uM
(1S,2R,3aR,4S,6aR)-4-[(2-amino-3,5-difluoroquinolin-7-yl)methyl]-2-(4-amino-5-fluoropyrrolo[2,3-d]pyrimidin-7-yl)-2,3,3a,4,5,6-hexahydro-1H-pentalene-1,6a-diol	1749891: Inhibition of PRMT5 (unknown origin) assessed as inhibition of symmetric dimethylation of arginine incubated for 3 days by fluorescence based cellular target engagement assay	ec50	0.0008	uM
6-(6-azaspiro[2.5]octane-6-carbonyl)-2-[(2R)-2-hydroxy-2-[(3S)-1,2,3,4-tetrahydroisoquinolin-3-yl]ethyl]-4,4-dimethyl-3H-isoquinolin-1-one	1997234: Inhibition of PRMT5 in human Z138 cells assessed as decrease in sDMA modification incubated for 2 days by fluorescence based assay	ic50	0.0008	uM
(2R,3R,3aS,6S,6aR)-6-(2-amino-3-fluoroquinolin-7-yl)oxy-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2,3,4,5,6,6a-hexahydrocyclopenta[b]furan-3,3a-diol	1749891: Inhibition of PRMT5 (unknown origin) assessed as inhibition of symmetric dimethylation of arginine incubated for 3 days by fluorescence based cellular target engagement assay	ec50	0.0009	uM
(1S,2R,3aR,4S,6aR)-4-[(2-amino-3-fluoroquinolin-7-yl)methyl]-2-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-2,3,3a,4,5,6-hexahydro-1H-pentalene-1,6a-diol	1749891: Inhibition of PRMT5 (unknown origin) assessed as inhibition of symmetric dimethylation of arginine incubated for 3 days by fluorescence based cellular target engagement assay	ec50	0.0009	uM
(1S,2R,3aR,4S,6aR)-4-[(2-amino-3-chloroquinolin-7-yl)methyl]-2-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-2,3,3a,4,5,6-hexahydro-1H-pentalene-1,6a-diol	1749891: Inhibition of PRMT5 (unknown origin) assessed as inhibition of symmetric dimethylation of arginine incubated for 3 days by fluorescence based cellular target engagement assay	ec50	0.0009	uM
1-[4-[[4-[(3S,4S)-4-(3,4-dihydro-1H-isoquinolin-2-yl)-3-hydroxypiperidine-1-carbonyl]-5-fluoro-2-pyridinyl]amino]piperidin-1-yl]ethanone	1997243: Inhibition of full-length recombinant PRMT5/full-length recombinant MEP50 (unknown origin) expressed in baculovirus infected Sf21 cells using biotinylated H4R3(Mel) peptide as substrate preincubated for 60 mins followed by substrate addition and measured for 150 minutes in the presence of SAM by methylation assay	ec50	0.0009	uM
(2R,3R,4S,5R)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(R)-(3,4-difluorophenyl)-hydroxymethyl]oxolane-3,4-diol	1593836: Inhibition of full length N-terminal FLAG-tagged PRMT5 (unknown origin)/MEP50 (unknown origin) expressed in baculovirus infected Sf21 insect cells using H4(1-21) peptide SGRGKGGKGLGKGGAKRHRKV as substrate measured after 25 minutes in the presence of [3H]SAM by liquid scintillation counting	ic50	0.0010	uM
(2R,3R,4S,5R)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(R)-(4-chlorophenyl)-hydroxymethyl]oxolane-3,4-diol	1593836: Inhibition of full length N-terminal FLAG-tagged PRMT5 (unknown origin)/MEP50 (unknown origin) expressed in baculovirus infected Sf21 insect cells using H4(1-21) peptide SGRGKGGKGLGKGGAKRHRKV as substrate measured after 25 minutes in the presence of [3H]SAM by liquid scintillation counting	ic50	0.0010	uM
(2R,3S,4R,5R)-2-[(R)-hydroxy(1,2,3,4-tetrahydroisoquinolin-8-yl)methyl]-5-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)oxolane-3,4-diol	1593837: Inhibition of PRMT5 (unknown origin)	ic50	0.0010	uM
(1S,2S,3S,5R)-3-[[6-(difluoromethyl)-5-fluoro-4-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl]oxy]-5-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol	1593837: Inhibition of PRMT5 (unknown origin)	ic50	0.0010	uM
(1S,2S,3R,5S)-3-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-5-(1,2,3,4-tetrahydroisoquinolin-8-yloxy)cyclopentane-1,2-diol	1593837: Inhibition of PRMT5 (unknown origin)	ic50	0.0010	uM
(1S,2S,3S,5R)-3-[(5-fluoro-6-methoxy-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy]-5-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol	1593837: Inhibition of PRMT5 (unknown origin)	ic50	0.0010	uM
(1S,2S,3S,5R)-3-[[6-(difluoromethoxy)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl]oxy]-5-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol	1593837: Inhibition of PRMT5 (unknown origin)	ic50	0.0010	uM
(1S,2S,3S,5R)-3-[(6-bromo-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy]-5-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol	1593837: Inhibition of PRMT5 (unknown origin)	ic50	0.0010	uM
8-[(1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]oxy-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile	1593837: Inhibition of PRMT5 (unknown origin)	ic50	0.0010	uM
(1S,2S,3S,5R)-3-[[6-(difluoromethyl)-1,2,3,4-tetrahydroisoquinolin-8-yl]oxy]-5-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol	1593837: Inhibition of PRMT5 (unknown origin)	ic50	0.0010	uM
(1S,2R,3aR,4S,6aR)-4-[(2-amino-3-fluoroquinolin-7-yl)methyl]-2-(4-amino-5-methylpyrrolo[2,3-d]pyrimidin-7-yl)-2,3,3a,4,5,6-hexahydro-1H-pentalene-1,6a-diol	1749891: Inhibition of PRMT5 (unknown origin) assessed as inhibition of symmetric dimethylation of arginine incubated for 3 days by fluorescence based cellular target engagement assay	ec50	0.0010	uM
N-(6-amino-5-methyl-3-pyridinyl)-2-[(2R,5S)-2-(1,3-benzothiazol-5-yl)-5-methylpiperidin-1-yl]-2-oxoacetamide	2104822: Substrate competitive inhibition of human PRMT5/MEP50 complex preincubated for 30 mins with [3H]SAM followed by incubation with 1 uM histone H4 (1 to 21) peptide for 2.5 hrs by radioactive flash plate based scintillation counting analysis	ki	0.0010	uM
3-[(2-amino-3-methylquinolin-7-yl)methyl]-N-methyl-2-oxo-N-phenyl-1,3-oxazole-4-carboxamide	1875140: Inhibition of PRMT5 methyltransferase activity in human MTAP -/- Calu-6 cells assessed as reduction in SmB SDMA levels measured after 2 days by HTRF based assay	ic50	0.0010	uM
2-[[2-(diaminomethylideneamino)-1,3-thiazol-5-yl]methyl]-N-[(4-fluorophenyl)methyl]-3-oxo-1H-isoindole-1-carboxamide	2113479: Binding affinity to apo PRMT5 (1 to 637 residues)(unknown origin) expressed in baculovirus infected Sf21 insect cells assessed as dissociation constant in presence of MTA by SPR analysis	kd	0.0010	uM
(1S,2R,3aR,4S,6aR)-4-[(2-amino-3-bromoquinolin-7-yl)methyl]-2-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-2,3,3a,4,5,6-hexahydro-1H-pentalene-1,6a-diol	1749891: Inhibition of PRMT5 (unknown origin) assessed as inhibition of symmetric dimethylation of arginine incubated for 3 days by fluorescence based cellular target engagement assay	ec50	0.0011	uM
(1S,2S,3S,5R)-3-[(4-fluoro-5-propan-2-yl-2,3-dihydro-1H-indol-7-yl)oxy]-5-pyrrolo[2,3-d]pyrimidin-7-ylcyclopentane-1,2-diol	2074356: Inhibition of PRMT5 (unknown origin)	ic50	0.0011	uM
(2R,3R,4S,5S)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R)-6-chloro-3,4-dihydro-1H-isochromen-1-yl]oxolane-3,4-diol	1997204: Inhibition of PRMT5 in human U-87 MG cells incubated for 4 mins by western blot analysis	ic50	0.0012	uM
(2R,3R,3aS,6S,6aR)-6-[(2-amino-3-chloroquinolin-7-yl)methyl]-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2,3,4,5,6,6a-hexahydrocyclopenta[b]furan-3,3a-diol	1749891: Inhibition of PRMT5 (unknown origin) assessed as inhibition of symmetric dimethylation of arginine incubated for 3 days by fluorescence based cellular target engagement assay	ec50	0.0012	uM
(2R,3R,3aS,6S,6aR)-6-(2-amino-3-bromoquinolin-7-yl)oxy-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2,3,4,5,6,6a-hexahydrocyclopenta[b]furan-3,3a-diol	1749891: Inhibition of PRMT5 (unknown origin) assessed as inhibition of symmetric dimethylation of arginine incubated for 3 days by fluorescence based cellular target engagement assay	ec50	0.0012	uM
(2R,3R,3aS,6S,6aR)-6-(2-amino-3-chloroquinolin-7-yl)oxy-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2,3,4,5,6,6a-hexahydrocyclopenta[b]furan-3,3a-diol	1749891: Inhibition of PRMT5 (unknown origin) assessed as inhibition of symmetric dimethylation of arginine incubated for 3 days by fluorescence based cellular target engagement assay	ec50	0.0012	uM

CTD chemical–gene interactions

67 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
GSK3235025	decreases activity, decreases expression	5
bisphenol A	affects expression, decreases expression	3
Ribavirin	decreases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Valproic Acid	increases expression	2
Aflatoxin B1	increases expression, decreases methylation	2
aristolochic acid I	increases expression	1
OTX015	decreases reaction, decreases expression, affects binding	1
bisphenol F	increases expression	1
JNJ-64619178	decreases activity	1
lly-283	decreases activity	1
2,4,6-tribromophenol	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
sodium arsenate	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression, affects localization, increases expression	1
sodium arsenite	decreases expression	1
perfluorooctanoic acid	decreases expression	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
beta-methylcholine	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
cylindrospermopsin	increases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
deguelin	increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
abrine	increases expression	1
hexabrominated diphenyl ether 153	increases expression	1
PP242	increases activity	1

ChEMBL screening assays

655 unique, capped per target: 624 binding, 30 functional, 1 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1804753	Binding	Inhibition of PRMT5-mediated methylation of histone H4 at 100 uM after 90 mins by scintillation counting in presence of S-adenosyl-l-[methyl-3H]methionine	Novel 3,5-bis(bromohydroxybenzylidene)piperidin-4-ones as coactivator-associated arginine methyltransferase 1 inhibitors: enzyme selectivity and cellular activity. — J Med Chem
CHEMBL5210098	Functional	Affinity Phenotypic Cellular interaction (MTT assay (cell proliferation in Z-138 cells)) EUB0000198b PRMT5	Affinity Phenotypic Cellular Literature for EUbOPEN Chemogenomics Library wave 3
CHEMBL5547649	Toxicity	Inhibition of PRMT5 in human HAP1 cells harboring wild type MTAP incubated for 24 hrs by SDMA in-cell western assay	Discovery of TNG908: A Selective, Brain Penetrant, MTA-Cooperative PRMT5 Inhibitor That Is Synthetically Lethal with MTAP-Deleted Cancers. — J Med Chem

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.