PSMB4

Summary

PSMB4 (proteasome 20S subunit beta 4, HGNC:9541) is a protein-coding gene on chromosome 1q21.3, encoding Proteasome subunit beta type-4 (P28070). Non-catalytic component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. It is a common-essential gene (DepMap: required in 100.0% of cancer cell lines).

The proteasome is a multicatalytic proteinase complex with a highly ordered ring-shaped 20S core structure. The core structure is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes a member of the proteasome B-type family, also known as the T1B family, that is a 20S core beta subunit.

Source: NCBI Gene 5692 — RefSeq curated summary.

At a glance

• Gene–disease (curated): proteasome-associated autoinflammatory syndrome 3 (Limited, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 299 total — 2 pathogenic
• Phenotypes (HPO): 26
• Druggable target: yes — 5 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 100.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_002796

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9541
Approved symbol	PSMB4
Name	proteasome 20S subunit beta 4
Location	1q21.3
Locus type	gene with protein product
Status	Approved
Aliases	HN3, PROS26
Ensembl gene	ENSG00000159377
Ensembl biotype	protein_coding
OMIM	602177
Entrez	5692

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 6 retained_intron, 4 protein_coding

ENST00000290541, ENST00000466425, ENST00000474100, ENST00000476467, ENST00000493673, ENST00000495288, ENST00000495805, ENST00000933662, ENST00000933663, ENST00000933664

RefSeq mRNA: 1 — MANE Select: NM_002796 NM_002796

CCDS: CCDS996

Canonical transcript exons

ENST00000290541 — 7 exons

Exon	Start	End
ENSE00001045218	151401239	151401355
ENSE00001850075	151401817	151401937
ENSE00001942667	151399573	151399727
ENSE00003517020	151399981	151400187
ENSE00003522405	151401542	151401630
ENSE00003527118	151400764	151400845
ENSE00003560860	151400442	151400588

Expression profiles

Bgee: expression breadth ubiquitous, 300 present calls, max score 99.51.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 142.2616 / max 1567.9015, expressed in 1824 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
5226	142.2616	1824

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
epithelium of nasopharynx	UBERON:0001951	99.51	gold quality
endometrium epithelium	UBERON:0004811	99.51	gold quality
nasopharynx	UBERON:0001728	99.49	gold quality
right adrenal gland	UBERON:0001233	99.21	gold quality
adenohypophysis	UBERON:0002196	99.21	gold quality
palpebral conjunctiva	UBERON:0001812	99.20	gold quality
mucosa of stomach	UBERON:0001199	99.19	gold quality
body of uterus	UBERON:0009853	99.19	gold quality
right adrenal gland cortex	UBERON:0035827	99.18	gold quality
smooth muscle tissue	UBERON:0001135	99.17	gold quality
left adrenal gland	UBERON:0001234	99.17	gold quality
left adrenal gland cortex	UBERON:0035825	99.17	gold quality
eye	UBERON:0000970	99.15	gold quality
pituitary gland	UBERON:0000007	99.11	gold quality
muscle layer of sigmoid colon	UBERON:0035805	99.11	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.11	gold quality
endocervix	UBERON:0000458	99.10	gold quality
left uterine tube	UBERON:0001303	99.10	gold quality
skin of leg	UBERON:0001511	99.10	gold quality
lower esophagus	UBERON:0013473	99.10	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.10	gold quality
granulocyte	CL:0000094	99.07	gold quality
islet of Langerhans	UBERON:0000006	99.07	gold quality
adrenal cortex	UBERON:0001235	99.07	gold quality
right ovary	UBERON:0002118	99.07	gold quality
metanephros cortex	UBERON:0010533	99.06	gold quality
skin of abdomen	UBERON:0001416	99.05	gold quality
gingival epithelium	UBERON:0001949	99.05	gold quality
adult organism	UBERON:0007023	99.04	gold quality
zone of skin	UBERON:0000014	99.03	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-111727	yes	1462.91
E-MTAB-7008	yes	1306.66
E-MTAB-8559	yes	556.85
E-MTAB-6379	no	1679.10
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

13 targeting PSMB4, 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-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-4480	99.42	66.02	735
HSA-MIR-10522-5P	99.26	68.50	2087
HSA-MIR-3973	99.20	69.19	1990
HSA-MIR-520G-3P	98.91	67.38	1914
HSA-MIR-520H	98.91	67.38	1914
HSA-MIR-4782-5P	98.35	69.33	1474
HSA-MIR-5706	98.35	69.33	1463
HSA-MIR-4277	98.34	67.17	1323
HSA-MIR-5007-5P	97.95	64.71	614

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 100.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 10)

• While 26 proteasome dysfunction is observed in Parkinson’s disease (PD), diverse mutations in the parkin gene are linked to early-onset autosomal-recessive forms of familial PD. (PMID:20810900)
• proteasome subunit beta type 4 (PSMB4), the beta7 subunit of the 20S core complex, was identified as a direct binding partner of CRBN. (PMID:23026050)
• Data indicate that recruitment of proteasomes into mutant huntingtin (mHTT) protein initiated inclusion bodies (IBs) was observed when the PSMB4-GFP was co-expressed with mHTT. (PMID:24291262)
• Taken together, our results demonstrated that PSMB4 regulated MM cell growth in part by activating NF-kappaB-miR-21 signaling, which may represent promising targets for novel specific therapies. (PMID:25656574)
• Our findings implied that PSMB4 is involved in the progression of EOC (epithelial ovarian cancer) and could serve as potential therapeutical target of EOC. These data suggested that PSMB4 may promote cell proliferation via the NF-kappaB-target gene in EOC (epithelial ovarian cancer) (PMID:26439929)
• We further identified miR-148b as a negative regulator of proteasome beta-4 subunit. Enforced expression of miR-148b resulted in vitro growth inhibition of melanoma cells, whereas this inhibition was further abolished by enforced expression of proteasome beta-4 subunit (PMID:28656878)
• PSMB4 knockdown decreased the expression levels of MMP2, MMP9 and cathepsin B and decreased proliferation, migration and invasion abilities in human GBM cells. (PMID:29414809)
• High PSMB4 expression is associated with breast cancer. (PMID:30066880)
• FoxM1 transcriptionally activates the PSMB4 expression level in cervical cancer cells. (PMID:31699366)
• Bassoon inhibits proteasome activity via interaction with PSMB4. (PMID:32651614)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	psmb4	ENSDARG00000054696
mus_musculus	Psmb4	ENSMUSG00000005779
rattus_norvegicus	Psmb4	ENSRNOG00000020979
drosophila_melanogaster	Prosbeta7	FBGN0250746
caenorhabditis_elegans	pbs-7	WBGENE00003953

Paralogs (18): PSMB1 (ENSG00000008018), PSMA4 (ENSG00000041357), PSMA3 (ENSG00000100567), PSMB5 (ENSG00000100804), PSMA6 (ENSG00000100902), PSMA7 (ENSG00000101182), PSMA2 (ENSG00000106588), PSMB2 (ENSG00000126067), PSMA1 (ENSG00000129084), PSMB7 (ENSG00000136930), PSMB6 (ENSG00000142507), PSMA5 (ENSG00000143106), PSMA8 (ENSG00000154611), PSMB8 (ENSG00000204264), PSMB10 (ENSG00000205220), PSMB11 (ENSG00000222028), PSMB9 (ENSG00000240065), PSMB3 (ENSG00000277791)

Protein

Protein identifiers

Proteasome subunit beta type-4 — P28070 (reviewed: P28070)

Alternative names: 26 kDa prosomal protein, Macropain beta chain, Multicatalytic endopeptidase complex beta chain, Proteasome beta chain, Proteasome chain 3, Proteasome subunit beta-7

All UniProt accessions (2): P28070, A0A140VK46

UniProt curated annotations — full annotation on UniProt →

Function. Non-catalytic component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). SMAD1/OAZ1/PSMB4 complex mediates the degradation of the CREBBP/EP300 repressor SNIP1.

Subunit / interactions. The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Forms a ternary complex with SMAD1 and OAZ1 before PSMB4 is incorporated into the 20S proteasome. Interacts with PRPF19. (Microbial infection) Interacts with HTLV-1 Tax protein. (Microbial infection) Interacts with HIV-1 Nef and Tat proteins.

Subcellular location. Cytoplasm. Nucleus.

Disease relevance. Proteasome-associated autoinflammatory syndrome 3 (PRAAS3) [MIM:617591] An autoinflammatory disorder characterized by onset in early infancy and recurrent fever, nodular dermatitis, myositis, panniculitis-induced lipodystrophy, lymphadenopathy, and immune dysregulation. Variable accompanying features may include joint contractures, hepatosplenomegaly, anemia, thrombocytopenia, recurrent infections, autoantibodies, and hypergammaglobulinemia. Some patients may have intracranial calcifications. PRAAS3 inheritance is autosomal recessive or digenic. The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry.

Induction. Up-regulated in fibrolamellar carcinomas.

Similarity. Belongs to the peptidase T1B family.

RefSeq proteins (1): NP_002787* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001353	Proteasome_sua/b	Family
IPR016050	Proteasome_bsu_CS	Conserved_site
IPR016295	Proteasome_beta4	Family
IPR023333	Proteasome_suB-type	Family
IPR029055	Ntn_hydrolases_N	Homologous_superfamily

Pfam: PF00227

UniProt features (33 total): strand 17, helix 6, sequence variant 4, modified residue 3, propeptide 1, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

146 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
5LE5	X-RAY DIFFRACTION	1.8
5LEY	X-RAY DIFFRACTION	1.9
5LF4	X-RAY DIFFRACTION	1.99
5LF1	X-RAY DIFFRACTION	2
5LF7	X-RAY DIFFRACTION	2
8UD9	ELECTRON MICROSCOPY	2.04
5LF6	X-RAY DIFFRACTION	2.07
5LF3	X-RAY DIFFRACTION	2.1
8BZL	X-RAY DIFFRACTION	2.14
5LEZ	X-RAY DIFFRACTION	2.19
5LEX	X-RAY DIFFRACTION	2.2
7AWE	X-RAY DIFFRACTION	2.29
5LF0	X-RAY DIFFRACTION	2.41
7B12	X-RAY DIFFRACTION	2.43
9K53	ELECTRON MICROSCOPY	2.5
9HMN	ELECTRON MICROSCOPY	2.55
4R3O	X-RAY DIFFRACTION	2.6
6RGQ	ELECTRON MICROSCOPY	2.6
9YUZ	ELECTRON MICROSCOPY	2.6
8CVR	ELECTRON MICROSCOPY	2.7
6KWY	ELECTRON MICROSCOPY	2.72
9MBP	ELECTRON MICROSCOPY	2.75
6E5B	X-RAY DIFFRACTION	2.77
7NAN	ELECTRON MICROSCOPY	2.8
8TM6	ELECTRON MICROSCOPY	2.8
9NKG	ELECTRON MICROSCOPY	2.8
8QYO	ELECTRON MICROSCOPY	2.84
8QYN	ELECTRON MICROSCOPY	2.88
4R67	X-RAY DIFFRACTION	2.89
7NAO	ELECTRON MICROSCOPY	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P28070-F1	87.70	0.81

Functional residue map

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

Post-translational modifications (3): 1, 26, 102

Function

Pathways and Gene Ontology

Reactome pathways

68 pathways

ID	Pathway
R-HSA-1169091	Activation of NF-kappaB in B cells
R-HSA-1234176	Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha
R-HSA-1236974	ER-Phagosome pathway
R-HSA-1236978	Cross-presentation of soluble exogenous antigens (endosomes)
R-HSA-174084	Autodegradation of Cdh1 by Cdh1:APC/C
R-HSA-174113	SCF-beta-TrCP mediated degradation of Emi1
R-HSA-174154	APC/C:Cdc20 mediated degradation of Securin
R-HSA-174178	APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1
R-HSA-174184	Cdc20:Phospho-APC/C mediated degradation of Cyclin A
R-HSA-180534	Vpu mediated degradation of CD4
R-HSA-180585	Vif-mediated degradation of APOBEC3G
R-HSA-187577	SCF(Skp2)-mediated degradation of p27/p21
R-HSA-195253	Degradation of beta-catenin by the destruction complex
R-HSA-202424	Downstream TCR signaling
R-HSA-211733	Regulation of activated PAK-2p34 by proteasome mediated degradation
R-HSA-2467813	Separation of Sister Chromatids
R-HSA-2871837	FCERI mediated NF-kB activation
R-HSA-349425	Autodegradation of the E3 ubiquitin ligase COP1
R-HSA-350562	Regulation of ornithine decarboxylase (ODC)
R-HSA-382556	ABC-family protein mediated transport
R-HSA-450408	AUF1 (hnRNP D0) binds and destabilizes mRNA
R-HSA-4608870	Asymmetric localization of PCP proteins
R-HSA-4641257	Degradation of AXIN
R-HSA-4641258	Degradation of DVL
R-HSA-5358346	Hedgehog ligand biogenesis
R-HSA-5362768	Hh mutants are degraded by ERAD
R-HSA-5607761	Dectin-1 mediated noncanonical NF-kB signaling
R-HSA-5607764	CLEC7A (Dectin-1) signaling
R-HSA-5610780	Degradation of GLI1 by the proteasome
R-HSA-5610783	Degradation of GLI2 by the proteasome

MSigDB gene sets: 542 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, MORF_MTA1, GOBP_REGULATION_OF_CELL_ACTIVATION, REACTOME_DNA_REPLICATION, REACTOME_SIGNALING_BY_NOTCH, REACTOME_APC_C_CDH1_MEDIATED_DEGRADATION_OF_CDC20_AND_OTHER_APC_C_CDH1_TARGETED_PROTEINS_IN_LATE_MITOSIS_EARLY_G1, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, JI_RESPONSE_TO_FSH_UP, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_INFLAMMATORY_RESPONSE_TO_ANTIGENIC_STIMULUS, MORF_MBD4, MORF_RAB5A, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE

GO Biological Process (3): negative regulation of inflammatory response to antigenic stimulus (GO:0002862), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), obsolete proteolysis involved in protein catabolic process (GO:0051603)

GO Molecular Function (2): lipopolysaccharide binding (GO:0001530), protein binding (GO:0005515)

GO Cellular Component (10): proteasome complex (GO:0000502), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), proteasome core complex (GO:0005839), proteasome core complex, beta-subunit complex (GO:0019774), ciliary basal body (GO:0036064), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-18 pathways:

Category	Pathways
Antigen processing-Cross presentation	2
APC/C-mediated degradation of cell cycle proteins	2
Host Interactions of HIV factors	2
Downstream signaling events of B Cell Receptor (BCR)	1
Cellular response to hypoxia	1
Regulation of APC/C activators between G1/S and early anaphase	1
APC/C:Cdc20 mediated degradation of mitotic proteins	1
APC:Cdc20 mediated degradation of cell cycle proteins prior to satisfation of the cell cycle checkpoint	1
Cyclin E associated events during G1/S transition	1
Cyclin A:Cdk2-associated events at S phase entry	1
Signaling by WNT	1
TCR signaling	1
Regulation of Apoptosis	1
Mitotic Anaphase	1
Fc epsilon receptor (FCERI) signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
intracellular protein-containing complex	2
intracellular membrane-bounded organelle	2
intracellular anatomical structure	2
cytoplasm	2
inflammatory response to antigenic stimulus	1
regulation of inflammatory response to antigenic stimulus	1
negative regulation of inflammatory response	1
negative regulation of immune response	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
lipid binding	1
carbohydrate derivative binding	1
binding	1
endopeptidase complex	1
nuclear lumen	1
proteasome complex	1
catalytic complex	1
proteasome core complex	1
protein-containing complex	1
microtubule organizing center	1
cilium	1
extracellular vesicle	1

Protein interactions and networks

STRING

2838 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PSMB4	PSMB2	P31145	992
PSMB4	PSMB3	P31147	976
PSMB4	PSMB5	P28074	957
PSMB4	PSMA3	P25788	941
PSMB4	PSMB1	P20618	941
PSMB4	PSMC2	P35998	896
PSMB4	PSMB9	P28065	895
PSMB4	PSMA1	P25786	875
PSMB4	PSMA6	P34062	872
PSMB4	PSMB6	P28072	853
PSMB4	PSMA5	P28066	819
PSMB4	PSMB7	Q99436	812
PSMB4	PSMA4	P25789	807
PSMB4	PSMA2	P25787	790
PSMB4	PSMD12	O00232	779

IntAct

263 interactions, top by confidence:

A	B	Type	Score
PSMA1	PSMA7	psi-mi:“MI:0915”(physical association)	0.950
PSMA1	PSMA7	psi-mi:“MI:0914”(association)	0.950
PSMA1	PSMA7	psi-mi:“MI:2364”(proximity)	0.950
STK24	STRN	psi-mi:“MI:0914”(association)	0.870
PSMA2	PSMA7	psi-mi:“MI:0914”(association)	0.850
UCHL5	PSMD11	psi-mi:“MI:0914”(association)	0.840
PSMB1	PSMB4	psi-mi:“MI:0915”(physical association)	0.800
PSMA5	PSMA7	psi-mi:“MI:0914”(association)	0.800
PSMB7	PSMA7	psi-mi:“MI:0914”(association)	0.790
PSMB2	PSMD11	psi-mi:“MI:0914”(association)	0.730
POMP	PSMA7	psi-mi:“MI:0915”(physical association)	0.720
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
PSMB4	PSMA3	psi-mi:“MI:0915”(physical association)	0.670

BioGRID (505): PSMB4 (Two-hybrid), FSD2 (Two-hybrid), PSMB4 (Affinity Capture-MS), PSMB4 (Affinity Capture-MS), PSMB4 (Affinity Capture-MS), PSMB2 (Affinity Capture-MS), PSMD13 (Affinity Capture-MS), PSMA2 (Affinity Capture-MS), PSMA3 (Affinity Capture-MS), PSMB1 (Affinity Capture-MS), PSMA6 (Affinity Capture-MS), PSME4 (Affinity Capture-MS), PSMA8 (Affinity Capture-MS), PSMA7 (Affinity Capture-MS), PSMD11 (Affinity Capture-MS)

ESM2 similar proteins: A4YJV0, A5E8F2, B6JAL5, B8BJ39, B8BM17, O08810, O09061, O23714, O24633, O80526, O81147, P18421, P20618, P28024, P28070, P34067, P40304, P40307, P49721, P99026, Q01217, Q2KHU3, Q2QNG7, Q2QXR8, Q2QZ86, Q2RAK2, Q2TBX6, Q3SWE6, Q3SX43, Q3T108, Q5E9K0, Q5F3X4, Q5RCW2, Q63486, Q6DRF3, Q7DLR9, Q7L523, Q80X95, Q89WM9, Q8K1R3

Diamond homologs: P28024, P28070, P30657, P34067, P99026, Q29384, Q3T108, Q556Q0, Q7DLR9, Q8SS01, Q9USQ9, Q9VNA5, P25043, O57983, Q8SR11, Q9V247, Q9YES4, B1L6X8, B6YXV3, C5A2D5, C6A3R1, O50110, P28064, A0LU50, C7R403, D1A3V2, Q74MP5, A1RX71, A4YJ04, A8M8R5, B1YDJ0, Q9V0N9

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PSMB4	“form complex”	“26S Proteasome”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 116 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
Antigen processing: Ub, ATP-independent proteasomal degradation	9	67.6×	3e-14
Autodegradation of the E3 ubiquitin ligase COP1	15	52.4×	3e-20
Regulation of activated PAK-2p34 by proteasome mediated degradation	14	51.3×	1e-19
Regulation of ornithine decarboxylase (ODC)	14	50.1×	1e-19
FBXL7 down-regulates AURKA during mitotic entry and in early mitosis	15	49.0×	4e-20
GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2	15	49.0×	4e-20
Vpu mediated degradation of CD4	14	48.9×	2e-19
Ubiquitin-dependent degradation of Cyclin D	14	48.9×	2e-19

GO biological processes:

GO term	Partners	Fold	FDR
proteasome-mediated ubiquitin-dependent protein catabolic process	19	9.9×	5e-11

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	156
Likely benign	104
Benign	11

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
548955	NM_002796.3(PSMB4):c.636_644del (p.Asp212_Val214del)	Pathogenic
548958	NM_002796.3(PSMB4):c.666C>A (p.Tyr222Ter)	Pathogenic

SpliceAI

678 predictions. Top by Δscore:

Variant	Effect	Δscore
1:151399728:G:GG	donor_gain	1.0000
1:151399977:TTA:T	acceptor_loss	1.0000
1:151399978:TAG:T	acceptor_loss	1.0000
1:151399979:A:AG	acceptor_gain	1.0000
1:151399979:AG:A	acceptor_gain	1.0000
1:151399980:G:GA	acceptor_gain	1.0000
1:151399980:GG:G	acceptor_gain	1.0000
1:151400183:ATGGT:A	donor_gain	1.0000
1:151400184:TGGT:T	donor_gain	1.0000
1:151400185:GGTG:G	donor_gain	1.0000
1:151400186:GT:G	donor_gain	1.0000
1:151400186:GTGTA:G	donor_loss	1.0000
1:151400187:TG:T	donor_loss	1.0000
1:151400188:G:GC	donor_loss	1.0000
1:151400188:G:GG	donor_gain	1.0000
1:151400189:TAAGT:T	donor_loss	1.0000
1:151400216:TTCCC:T	donor_gain	1.0000
1:151400232:G:T	donor_gain	1.0000
1:151400570:GC:G	donor_gain	1.0000
1:151401228:A:AG	acceptor_gain	1.0000
1:151401540:A:AG	acceptor_gain	1.0000
1:151401541:G:GG	acceptor_gain	1.0000
1:151401541:GTTTC:G	acceptor_gain	1.0000
1:151401627:TCAG:T	donor_gain	1.0000
1:151401627:TCAGG:T	donor_loss	1.0000
1:151401628:CAGGT:C	donor_loss	1.0000
1:151401629:AGG:A	donor_loss	1.0000
1:151401630:GGTG:G	donor_loss	1.0000
1:151401631:G:GG	donor_gain	1.0000
1:151401632:T:A	donor_loss	1.0000

AlphaMissense

1700 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:151400043:C:A	A68D	0.999
1:151400045:G:C	A69P	0.999
1:151400048:G:C	D70H	0.999
1:151400049:A:T	D70V	0.999
1:151400096:C:A	R86S	0.999
1:151400841:C:A	A191D	0.999
1:151401333:G:C	R224P	0.999
1:151401608:T:A	W254R	0.999
1:151401608:T:C	W254R	0.999
1:151401610:G:C	W254C	0.999
1:151401610:G:T	W254C	0.999
1:151399997:G:T	G53W	0.998
1:151400007:T:A	V56D	0.998
1:151400021:T:C	F61L	0.998
1:151400023:C:A	F61L	0.998
1:151400023:C:G	F61L	0.998
1:151400042:G:C	A68P	0.998
1:151400048:G:T	D70Y	0.998
1:151400049:A:C	D70A	0.998
1:151400081:T:C	F81L	0.998
1:151400083:C:A	F81L	0.998
1:151400083:C:G	F81L	0.998
1:151400139:G:T	G100V	0.998
1:151400150:G:C	D104H	0.998
1:151400151:A:T	D104V	0.998
1:151400504:T:C	L137P	0.998
1:151400789:G:C	G174R	0.998
1:151400790:G:A	G174D	0.998
1:151400790:G:T	G174V	0.998
1:151400829:G:A	G187D	0.998

dbSNP variants (sampled 300 via entrez): RS1002043713 (1:151402390 G>A), RS1002319664 (1:151399169 A>G), RS1002631433 (1:151398836 A>T), RS1003461822 (1:151398673 C>G), RS1003502063 (1:151402423 A>G), RS1003888176 (1:151397861 A>G), RS1005567531 (1:151401005 C>G,T), RS1005795960 (1:151398310 A>G), RS1005911667 (1:151401175 T>C), RS1005931511 (1:151400715 T>C), RS1006243170 (1:151397943 G>A), RS1007493165 (1:151401286 C>A,G,T), RS1008002717 (1:151399802 C>T), RS1008360177 (1:151399978 T>C), RS1009025058 (1:151401442 C>T)

Disease associations

OMIM: gene MIM:602177 | disease phenotypes: MIM:617591, MIM:256040

GenCC curated gene-disease

Disease	Classification	Inheritance
proteasome-associated autoinflammatory syndrome 3	Limited	Autosomal recessive

Mondo (4): Dravet syndrome (MONDO:0100135), proteasome-associated autoinflammatory syndrome 3 (MONDO:0054699), muscular dystrophy (MONDO:0020121), proteasome-associated autoinflammatory syndrome 1 (MONDO:0054698)

Orphanet (6): Dravet syndrome (Orphanet:33069), Muscular dystrophy (Orphanet:98473), Nakajo-Nishimura syndrome (Orphanet:2615), Proteasome-associated autoinflammatory syndrome (Orphanet:324977), JMP syndrome (Orphanet:324999), CANDLE syndrome (Orphanet:325004)

HPO phenotypes

26 total (26 of 26 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000246	Sinusitis
HP:0000509	Conjunctivitis
HP:0000956	Acanthosis nigricans
HP:0000988	Skin rash
HP:0001369	Arthritis
HP:0001371	Flexion contracture
HP:0001508	Failure to thrive
HP:0001744	Splenomegaly
HP:0001873	Thrombocytopenia
HP:0001888	Decreased total lymphocyte count
HP:0001903	Anemia
HP:0001954	Recurrent fever
HP:0002155	Hypertriglyceridemia
HP:0002240	Hepatomegaly
HP:0002716	Lymphadenopathy
HP:0002719	Recurrent infections
HP:0002829	Arthralgia
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003565	Elevated erythrocyte sedimentation rate
HP:0009125	Lipodystrophy
HP:0010702	Increased circulating immunoglobulin concentration
HP:0012490	Panniculitis
HP:0025131	Finger swelling
HP:0100539	Periorbital edema
HP:0100614	Myositis

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002041_2	Blood trace element (Cu levels)	3.000000e-20
GCST005951_38	Body mass index	4.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005267	serum copper measurement
EFO:0004340	body mass index

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D009136	Muscular Dystrophies	C05.651.534.500; C10.668.491.175.500; C16.320.577

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2364701 (PROTEIN COMPLEX), CHEMBL3831201 (PROTEIN COMPLEX GROUP), CHEMBL4879435 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

5 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 41,720 (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
CHEMBL325041	BORTEZOMIB	4	13,120
CHEMBL451887	CARFILZOMIB	4	12,508
CHEMBL2141296	IXAZOMIB	3	6,022
CHEMBL371405	MARIZOMIB	3	7,332
CHEMBL2103884	OPROZOMIB	2	2,738

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2296840	PSMB4		0.00	0

ChEMBL bioactivities

313 potent at pChembl≥5 of 339 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.22	IC50	0.6	nM	CINNABARAMIDE G
9.22	Ki	0.6	nM	CHEMBL5624541
9.22	Ki	0.6	nM	BORTEZOMIB
9.04	IC50	0.92	nM	CHEMBL4102324
9.00	IC50	1	nM	CINNABARAMIDE A
8.89	IC50	1.3	nM	MARIZOMIB
8.82	IC50	1.5	nM	CHEMBL4460323
8.70	IC50	2	nM	CHEMBL307387
8.66	IC50	2.2	nM	CHEMBL5419917
8.62	IC50	2.4	nM	CHEMBL4517600
8.62	IC50	2.4	nM	BORTEZOMIB
8.62	IC50	2.4	nM	CHEMBL5413513
8.60	IC50	2.5	nM	CHEMBL4587036
8.59	IC50	2.56	nM	BORTEZOMIB
8.57	IC50	2.7	nM	CHEMBL3237863
8.57	IC50	2.7	nM	CHEMBL5394365
8.52	IC50	3	nM	BORTEZOMIB
8.47	IC50	3.4	nM	CHEMBL4444107
8.47	IC50	3.4	nM	CHEMBL6143686
8.46	IC50	3.43	nM	CHEMBL5197285
8.44	IC50	3.6	nM	CHEMBL4541038
8.41	IC50	3.9	nM	CHEMBL3237862
8.41	IC50	3.9	nM	CHEMBL4547405
8.40	IC50	4	nM	CHEMBL5406440
8.39	IC50	4.1	nM	CHEMBL3237864
8.39	IC50	4.1	nM	CHEMBL3237867
8.39	IC50	4.03	nM	CHEMBL5171225
8.37	IC50	4.28	nM	CHEMBL4581126
8.34	IC50	4.6	nM	CHEMBL4542373
8.34	IC50	4.6	nM	CHEMBL4558648
8.32	IC50	4.8	nM	CHEMBL3237873
8.32	IC50	4.8	nM	CHEMBL4467618
8.30	IC50	5	nM	CHEMBL5398681
8.29	IC50	5.1	nM	CHEMBL3237865
8.29	IC50	5.15	nM	CHEMBL5186240
8.28	IC50	5.2	nM	CHEMBL5429323
8.28	IC50	5.2	nM	CHEMBL5431451
8.25	IC50	5.6	nM	CHEMBL5423645
8.24	IC50	5.7	nM	CHEMBL3237866
8.24	IC50	5.7	nM	CHEMBL3237860
8.23	IC50	5.9	nM	CHEMBL3237868
8.22	IC50	6	nM	CINNABARAMIDE F
8.22	IC50	6	nM	CHEMBL5412037
8.22	IC50	6	nM	CHEMBL74336
8.20	IC50	6.3	nM	CHEMBL5440712
8.19	IC50	6.4	nM	CHEMBL4447701
8.19	IC50	6.4	nM	CHEMBL4435814
8.19	IC50	6.5	nM	CHEMBL4436430
8.19	IC50	6.5	nM	IXAZOMIB
8.16	IC50	6.91	nM	BORTEZOMIB

PubChem BioAssay actives

281 with measured affinity, of 820 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
methyl (2R)-2-acetamido-3-[(2R,3S,4R)-2-[(S)-[(1S)-cyclohex-2-en-1-yl]-hydroxymethyl]-4-hexyl-3-hydroxy-3-methyl-5-oxopyrrolidine-2-carbonyl]sulfanylpropanoate	277357: Inhibition of human 20S proteasome	ic50	0.0006	uM
[(1R)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]-(pyrazine-2-carbonyl)amino]-3-methylbutyl]boronic acid	2131634: Binding affinity to 20s proteosome (unknown origin) assessed as inhibition constant	ki	0.0006	uM
1-N-[(2S)-1-[[(2S)-1-[(2-chlorophenyl)methylamino]-1-oxo-4-phenylbutan-2-yl]amino]-4-(2,2-dimethylpropylamino)-1,4-dioxobutan-2-yl]-4-N-(1,3-thiazol-2-yl)piperidine-1,4-dicarboxamide	1903224: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-Leu Leu-Val-Tyr-AMC as substrate preincubated for 15 mins followed by substrate addition measured by fluorescence assay	ic50	0.0009	uM
(1R,4R,5S)-1-[(S)-[(1S)-cyclohex-2-en-1-yl]-hydroxymethyl]-4-hexyl-5-methyl-6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione	277357: Inhibition of human 20S proteasome	ic50	0.0010	uM
(1R,4R,5S)-4-(2-chloroethyl)-1-[(S)-[(1S)-cyclohex-2-en-1-yl]-hydroxymethyl]-5-methyl-6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione	1853759: Inhibition of 20S proteasome (unknown origin) by fluorescence based assay	ic50	0.0013	uM
1-N-[(2S)-4-methyl-1-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]-4-N-(1,3-thiazol-2-yl)piperidine-1,4-dicarboxamide	1624025: Inhibition of human 20S proteasome preincubated for 15 mins followed by substrate addition	ic50	0.0015	uM
N-[5-[[amino(nitramido)methylidene]amino]-1-[(4-methyl-1-oxopentan-2-yl)amino]-1-oxopentan-2-yl]-2-cyclopentyl-10-(1,3-dioxoisoindol-2-yl)decanamide	3028: Compound was evaluated for inhibitory activity against 20S proteasome from human liver and brain	ic50	0.0020	uM
4-[(1R)-1-[[2-[[2,5-bis(trifluoromethyl)benzoyl]amino]-3-cyclopropylpropanoyl]amino]-3-methylbutyl]-2-methyl-3,5,10-trioxa-4-boratricyclo[5.2.1.02,6]decane-8-carboxylic acid	2033891: Inhibition of human 20S proteasome chymotrypsin-like activity using Suc-Leu-Leu-Val-Tyr-AMC as fluorogenic peptide pre-incubated for 10 mins with compound followed by substrate addition for 60 mins by spectrofluorimetric analysis	ic50	0.0022	uM
4-N-(4-benzoylphenyl)-1-N-[(2S)-4-methyl-1-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]piperidine-1,4-dicarboxamide	1624025: Inhibition of human 20S proteasome preincubated for 15 mins followed by substrate addition	ic50	0.0024	uM
4-[(1R)-1-[[2-[[2,5-bis(trifluoromethyl)benzoyl]amino]-2-cyclopentylacetyl]amino]-3-methylbutyl]-2-methyl-3,5,10-trioxa-4-boratricyclo[5.2.1.02,6]decane-8-carboxylic acid	2033891: Inhibition of human 20S proteasome chymotrypsin-like activity using Suc-Leu-Leu-Val-Tyr-AMC as fluorogenic peptide pre-incubated for 10 mins with compound followed by substrate addition for 60 mins by spectrofluorimetric analysis	ic50	0.0024	uM
Bortezomib	1985684: Inhibition of 26S proteasome (unknown origin)	ic50	0.0024	uM
(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-acetamido-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]amino]-5-carbamimidamidopentanoyl]amino]-6-aminohexanoyl]amino]-6-aminohexanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-N-[(2S)-5-carbamimidamido-1-[[(2S)-5-carbamimidamido-1-[[(2S)-5-carbamimidamido-1-[[2-[[2-[[2-[[(2S)-4-methyl-1-[[(2S)-4-methyl-1-[[(2S)-4-methyl-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-2-oxoethyl]amino]-2-oxoethyl]amino]-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]pentanediamide	1559513: Inhibition of human 20S proteasome using Suc-LLVY-AMC as substrate measured every 5 mins for 120 mins by fluorescence based assay	ic50	0.0025	uM
4-[(1R)-1-[[2-[[2,5-bis(trifluoromethyl)benzoyl]amino]-2-cyclopropylacetyl]amino]-3-methylbutyl]-2-methyl-3,5,10-trioxa-4-boratricyclo[5.2.1.02,6]decane-8-carboxylic acid	2033891: Inhibition of human 20S proteasome chymotrypsin-like activity using Suc-Leu-Leu-Val-Tyr-AMC as fluorogenic peptide pre-incubated for 10 mins with compound followed by substrate addition for 60 mins by spectrofluorimetric analysis	ic50	0.0027	uM
(2S)-2-acetamido-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[4-phenylmethoxy-3-(phenylmethoxymethyl)butyl]butanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0027	uM
4-N-(4-fluorophenyl)-1-N-[(2S)-4-methyl-1-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]piperidine-1,4-dicarboxamide	1624025: Inhibition of human 20S proteasome preincubated for 15 mins followed by substrate addition	ic50	0.0034	uM
1-N-[(2S)-4-(2,2-dimethylpropylamino)-1,4-dioxo-1-[[(2S)-1-oxo-4-phenyl-1-[[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]amino]butan-2-yl]amino]butan-2-yl]-4-N-methyl-4-N-(1,3-thiazol-2-yl)piperidine-1,4-dicarboxamide	1903224: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-Leu Leu-Val-Tyr-AMC as substrate preincubated for 15 mins followed by substrate addition measured by fluorescence assay	ic50	0.0034	uM
1-N-[(2S)-4-methyl-1-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]-4-N-pyridin-3-ylpiperidine-1,4-dicarboxamide	1624025: Inhibition of human 20S proteasome preincubated for 15 mins followed by substrate addition	ic50	0.0036	uM
4-N-(1,3-benzothiazol-2-yl)-1-N-[(2S)-4-methyl-1-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]piperidine-1,4-dicarboxamide	1624025: Inhibition of human 20S proteasome preincubated for 15 mins followed by substrate addition	ic50	0.0039	uM
(2S)-2-acetamido-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[3-phenylmethoxy-2-(phenylmethoxymethyl)propyl]butanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0039	uM
[(1R)-1-[[2-[(2,5-dibromobenzoyl)amino]acetyl]amino]-3-methylbutyl]boronic acid	2033891: Inhibition of human 20S proteasome chymotrypsin-like activity using Suc-Leu-Leu-Val-Tyr-AMC as fluorogenic peptide pre-incubated for 10 mins with compound followed by substrate addition for 60 mins by spectrofluorimetric analysis	ic50	0.0040	uM
1-N-[(2S)-4-(2,2-dimethylpropylamino)-1,4-dioxo-1-[[(2S)-1-oxo-4-phenyl-1-[[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]amino]butan-2-yl]amino]butan-2-yl]-4-N-pyridin-3-ylpiperidine-1,4-dicarboxamide	1903224: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-Leu Leu-Val-Tyr-AMC as substrate preincubated for 15 mins followed by substrate addition measured by fluorescence assay	ic50	0.0040	uM
(2S)-2-acetamido-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[5-phenylmethoxy-4-(phenylmethoxymethyl)pentyl]butanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0041	uM
(2S)-2-acetamido-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[5-phenylmethoxy-4-(phenylmethoxymethyl)pentyl]pentanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0041	uM
(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-acetamido-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]amino]-5-carbamimidamidopentanoyl]amino]-6-aminohexanoyl]amino]-6-aminohexanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-N-[(2S)-5-carbamimidamido-1-[[(2S)-5-carbamimidamido-1-[[(2S)-5-carbamimidamido-1-[[2-[[2-[[2-[[(2S)-3-(4-hydroxyphenyl)-1-[[(2S)-4-methyl-1-[[(2S)-1-[[(2S)-4-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-2-oxoethyl]amino]-2-oxoethyl]amino]-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]pentanediamide	1559513: Inhibition of human 20S proteasome using Suc-LLVY-AMC as substrate measured every 5 mins for 120 mins by fluorescence based assay	ic50	0.0043	uM
1-N-[(2S)-4-methyl-1-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]-4-N-(1,3,4-thiadiazol-2-yl)piperidine-1,4-dicarboxamide	1624025: Inhibition of human 20S proteasome preincubated for 15 mins followed by substrate addition	ic50	0.0046	uM
4-N-(4-chlorophenyl)-1-N-[(2S)-4-methyl-1-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]piperidine-1,4-dicarboxamide	1624025: Inhibition of human 20S proteasome preincubated for 15 mins followed by substrate addition	ic50	0.0046	uM
4-N-(4-methoxyphenyl)-1-N-[(2S)-4-methyl-1-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]piperidine-1,4-dicarboxamide	1624025: Inhibition of human 20S proteasome preincubated for 15 mins followed by substrate addition	ic50	0.0048	uM
(2S)-2-acetamido-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-(4-phenylmethoxybutyl)butanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0048	uM
[(1R)-1-[[2-[[2,5-bis(trifluoromethyl)benzoyl]amino]-3-cyclopropylpropanoyl]amino]-3-methylbutyl]boronic acid	2033891: Inhibition of human 20S proteasome chymotrypsin-like activity using Suc-Leu-Leu-Val-Tyr-AMC as fluorogenic peptide pre-incubated for 10 mins with compound followed by substrate addition for 60 mins by spectrofluorimetric analysis	ic50	0.0050	uM
(2S)-2-acetamido-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[3-phenylmethoxy-2-(phenylmethoxymethyl)propyl]pentanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0051	uM
(2S)-N’-(2,2-dimethylpropyl)-2-[[4-[methyl(pyridine-3-carbonyl)amino]piperidine-1-carbonyl]amino]-N-[(2S)-1-oxo-4-phenyl-1-[[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]amino]butan-2-yl]butanediamide	1903224: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-Leu Leu-Val-Tyr-AMC as substrate preincubated for 15 mins followed by substrate addition measured by fluorescence assay	ic50	0.0052	uM
4-[(1R)-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]-2-methyl-3,5,10-trioxa-4-boratricyclo[5.2.1.02,6]decane-8-carboxylic acid	2033891: Inhibition of human 20S proteasome chymotrypsin-like activity using Suc-Leu-Leu-Val-Tyr-AMC as fluorogenic peptide pre-incubated for 10 mins with compound followed by substrate addition for 60 mins by spectrofluorimetric analysis	ic50	0.0052	uM
[(1R)-1-[[2-[[2,5-bis(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-methylbutyl]boronic acid	2033891: Inhibition of human 20S proteasome chymotrypsin-like activity using Suc-Leu-Leu-Val-Tyr-AMC as fluorogenic peptide pre-incubated for 10 mins with compound followed by substrate addition for 60 mins by spectrofluorimetric analysis	ic50	0.0052	uM
[(1R)-1-[[2-[[2,5-bis(trifluoromethyl)benzoyl]amino]-2-cyclopropylacetyl]amino]-3-methylbutyl]boronic acid	2033891: Inhibition of human 20S proteasome chymotrypsin-like activity using Suc-Leu-Leu-Val-Tyr-AMC as fluorogenic peptide pre-incubated for 10 mins with compound followed by substrate addition for 60 mins by spectrofluorimetric analysis	ic50	0.0056	uM
(2S)-2-acetamido-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[4-phenylmethoxy-3-(phenylmethoxymethyl)butyl]pentanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0057	uM
benzyl N-[(2S)-1-[[(2R)-1-[(1R,2S)-2-[[(2R,3S)-3-[(2S)-butan-2-yl]-4-oxooxetane-2-carbonyl]amino]cyclopropyl]-4-phenylbutan-2-yl]amino]-1-oxopropan-2-yl]carbamate	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0057	uM
(2S)-2-[(2,5-dichlorobenzoyl)amino]-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[4-phenylmethoxy-3-(phenylmethoxymethyl)butyl]butanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0059	uM
(2R)-2-acetamido-3-[(2R,3S,4R)-2-[(S)-[(1S)-cyclohex-2-en-1-yl]-hydroxymethyl]-4-hexyl-3-hydroxy-3-methyl-5-oxopyrrolidine-2-carbonyl]sulfanylpropanoic acid	277357: Inhibition of human 20S proteasome	ic50	0.0060	uM
[(1R)-1-[[2-[[2,5-bis(trifluoromethyl)benzoyl]amino]-2-cyclopentylacetyl]amino]-3-methylbutyl]boronic acid	2033891: Inhibition of human 20S proteasome chymotrypsin-like activity using Suc-Leu-Leu-Val-Tyr-AMC as fluorogenic peptide pre-incubated for 10 mins with compound followed by substrate addition for 60 mins by spectrofluorimetric analysis	ic50	0.0060	uM
N-[5-[[amino(nitramido)methylidene]amino]-1-[(4-methyl-1-oxopentan-2-yl)amino]-1-oxopentan-2-yl]-10-cyano-2-cyclopentyldecanamide	3028: Compound was evaluated for inhibitory activity against 20S proteasome from human liver and brain	ic50	0.0060	uM
4-[(1R)-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]-3,5,10-trioxa-4-boratricyclo[5.2.1.02,6]decane-8-carboxylic acid	2033891: Inhibition of human 20S proteasome chymotrypsin-like activity using Suc-Leu-Leu-Val-Tyr-AMC as fluorogenic peptide pre-incubated for 10 mins with compound followed by substrate addition for 60 mins by spectrofluorimetric analysis	ic50	0.0063	uM
1-N-[(2S)-4-methyl-1-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]-4-N-(1,2-oxazol-3-yl)piperidine-1,4-dicarboxamide	1624025: Inhibition of human 20S proteasome preincubated for 15 mins followed by substrate addition	ic50	0.0064	uM
(2S)-2-[[(2S)-2-acetamido-3-(4-hydroxyphenyl)propanoyl]amino]-4-methyl-N-[(2S)-1-[[(2S)-4-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]pentanamide	1559513: Inhibition of human 20S proteasome using Suc-LLVY-AMC as substrate measured every 5 mins for 120 mins by fluorescence based assay	ic50	0.0064	uM
1-N-[(2S)-4-methyl-1-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]-4-N-pyrazin-2-ylpiperidine-1,4-dicarboxamide	1624025: Inhibition of human 20S proteasome preincubated for 15 mins followed by substrate addition	ic50	0.0065	uM
Ixazomib	2033891: Inhibition of human 20S proteasome chymotrypsin-like activity using Suc-Leu-Leu-Val-Tyr-AMC as fluorogenic peptide pre-incubated for 10 mins with compound followed by substrate addition for 60 mins by spectrofluorimetric analysis	ic50	0.0065	uM
4-N-(4-chlorophenyl)-1-N-[(2S)-4-(2,2-dimethylpropylamino)-1,4-dioxo-1-[[(2S)-1-oxo-4-phenyl-1-[[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]amino]butan-2-yl]amino]butan-2-yl]-4-N-methylpiperidine-1,4-dicarboxamide	1903224: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-Leu Leu-Val-Tyr-AMC as substrate preincubated for 15 mins followed by substrate addition measured by fluorescence assay	ic50	0.0069	uM
(2S)-N-[(2S,3R,4R)-3-hydroxy-5-[[(2S)-1-[(2-hydroxy-4-methoxyphenyl)methylamino]-3-methyl-1-oxobutan-2-yl]amino]-5-oxo-1-phenyl-4-[(3,4,5-trimethoxyphenyl)methylamino]pentan-2-yl]-3,3-dimethyl-2-[(2-naphthalen-1-ylacetyl)amino]butanamide	3027: Tested in vitro for inhibition of chymotrypsin like activity of purified human 20S proteasome	ic50	0.0070	uM
Carfilzomib	1770085: Inhibition of human 20S proteasome chymotrypsin-like activity in human RPMI-8226 cells using Suc-LLVY-AMC as fluorogenic substrate incubated for 3 hrs by fluorescence assay	ic50	0.0070	uM
(2S)-2-[[(2S)-3-(4-hydroxyphenyl)-2-[(2-naphthalen-1-ylacetyl)amino]propanoyl]amino]-N-[1-(4-hydroxyphenyl)-3-oxopropan-2-yl]-3-methylbutanamide	248827: Inhibitory concentration to inhibit chymotrypsin-like activity of 20S proteasome prepared from human leukemia HL-60 cells was determined	ic50	0.0070	uM
(2S)-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[4-phenylmethoxy-3-(phenylmethoxymethyl)butyl]-2-(pyrazine-2-carbonylamino)butanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0071	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
arsenite	increases reaction, increases methylation, affects binding	2
sodium arsenite	affects cotreatment, increases abundance, increases expression	2
Arsenic Trioxide	increases expression	2
Arsenic	decreases expression, increases abundance, affects cotreatment, increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
Particulate Matter	increases reaction, decreases expression, increases abundance, affects expression	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
nobiletin	decreases expression, decreases reaction	1
sodium arsenate	decreases reaction, decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression	1
trichostatin A	affects cotreatment, decreases expression	1
beta-lapachone	increases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
cobaltous chloride	increases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
arsenic trichloride	decreases expression, increases abundance	1
microcystin RR	decreases expression	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	increases expression	1
chloropicrin	decreases expression	1
poly(propyleneimine)	decreases expression	1
oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine	affects expression, increases reaction	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
stattic	decreases expression	1
EGFR tyrosine kinase inhibitor 324674	decreases reaction, increases expression	1
bisphenol AF	increases expression	1
Decitabine	decreases expression, affects cotreatment	1
Sunitinib	decreases expression	1

ChEMBL screening assays

171 unique, capped per target: 162 binding, 6 admet, 3 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3222879	Binding	Inhibition of human 20S proteasome using Suc-LLVY-AMC as substrate preincubated for 30 mins followed by substrate addition measured after 90 mins by fluorescence assay	Oxathiazole-2-one derivative of bortezomib: Synthesis, stability and proteasome inhibition activity — Medchemcomm
CHEMBL4736581	ADMET	Inhibition of human 20S proteasome stably expressed in HEK293 cells at 5 to 50 uM using succinyl-LLVY-AMC as substrate preincubated for 30 mins followed by substrate addition and measured at 3 mins interval for 30 mins by fluorescence assay	A covalent p97/VCP ATPase inhibitor can overcome resistance to CB-5083 and NMS-873 in colorectal cancer cells. — Eur J Med Chem
CHEMBL834792	Functional	Inhibitory concentration to inhibit trypsin-like activity of 20S proteasome from human leukemia HL-60 cells was determined	Structure-based design of derivatives of tyropeptin A as the potent and selective inhibitors of mammalian 20S proteasome. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05044819	PHASE4	ACTIVE_NOT_RECRUITING	Assessment of Potential for Chronic Liver Injury in Participants Treated With Epidiolex (Cannabidiol) Oral Solution
NCT06598449	PHASE4	RECRUITING	Assessment of Safety of the Use of Fenfluramine in Children With Dravet Syndrome Under 24 Months of Age
NCT06924827	PHASE4	NOT_YET_RECRUITING	A Study to Investigate the Transition of Children From ‘Artisanal Cannabidiol (CBD) to Epidiolex
NCT07112365	PHASE4	NOT_YET_RECRUITING	The FINTEPLA as an Anti-SUDEP Therapy in Dravet Syndrome Project
NCT01882400	PHASE4	COMPLETED	Assessment of Response to Treatment of Osteoporosis With Oral Bisphosphonates in Patients With Muscular Dystrophy
NCT00098475	PHASE3	ACTIVE_NOT_RECRUITING	Lenalidomide and Dexamethasone With or Without Thalidomide in Treating Patients With Multiple Myeloma
NCT00114101	PHASE3	ACTIVE_NOT_RECRUITING	Lenalidomide in Treating Patients With Multiple Myeloma Undergoing Autologous Stem Cell Transplant
NCT00644228	PHASE3	ACTIVE_NOT_RECRUITING	Lenalidomide and Dexamethasone With or Without Bortezomib in Treating Patients With Previously Untreated Multiple Myeloma
NCT00869206	PHASE3	COMPLETED	Zoledronic Acid in Treating Patients With Metastatic Breast Cancer, Metastatic Prostate Cancer, or Multiple Myeloma With Bone Involvement
NCT02091375	PHASE3	COMPLETED	Antiepileptic Efficacy Study of GWP42003-P in Children and Young Adults With Dravet Syndrome (GWPCARE1)
NCT02174094	PHASE3	WITHDRAWN	Clobazam as Adjunctive Therapy in Paediatric Patients Aged ≥1 to ≤16 Years With Dravet Syndrome
NCT02187809	PHASE3	TERMINATED	Safety and Tolerability of Clobazam as Adjunctive Therapy in Paediatric Patients Aged ≥1 to ≤16 Years With Dravet Syndrome
NCT02224573	PHASE3	COMPLETED	An Open Label Extension Study of Cannabidiol (GWP42003-P) in Children and Adults With Dravet or Lennox-Gastaut Syndromes
NCT02224703	PHASE3	COMPLETED	GWPCARE2 A Study to Investigate the Efficacy and Safety of Cannabidiol (GWP42003-P) in Children and Young Adults With Dravet Syndrome
NCT02318563	PHASE3	WITHDRAWN	Cannabidiol Oral Solution as an Adjunctive Therapy for Treatment of Participants With Inadequately Controlled Dravet Syndrome
NCT02682927	PHASE3	COMPLETED	A Trial of Two Fixed Doses of ZX008 (Fenfluramine HCl) in Children and Young Adults With Dravet Syndrome
NCT02823145	PHASE3	COMPLETED	An Open-Label Extension Trial to Assess the Long-Term Safety of ZX008 (Fenfluramine Hydrochloride HCl) Oral Solution in Children and Young Adults With Dravet Syndrome
NCT02926898	PHASE3	COMPLETED	A 2-Part Study to Investigate the Dose-Ranging Safety and Pharmacokinetics, Followed by the Efficacy and Safety of ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive Therapy in Children ≥ 2 Years Old and Young Adults With Dravet Syndrome
NCT03299842	PHASE3	TERMINATED	A Study to Assess the Usability of the Embrace Seizure Detection Watch in Children and Young Adults With Dravet Syndrome
NCT03936777	PHASE3	COMPLETED	A Study to Investigate the Long-Term Safety of ZX008 (Fenfluramine Hydrochloride) Oral Solution in Children and Adults With Epileptic Encephalopathy Including Dravet Syndrome and Lennox-Gastaut Syndrome
NCT04462770	PHASE3	RECRUITING	A Study of EPX-100 (Clemizole Hydrochloride) in Participants With Dravet Syndrome
NCT04611438	PHASE3	UNKNOWN	Research on Cognitive Effect of Cannabidiol on Dravet Syndrome and Lennox-Gastaut SyndromeGastaut Syndrome
NCT04940624	PHASE3	COMPLETED	A Study of Soticlestat as an Add-on Therapy in Children and Young Adults With Dravet Syndrome
NCT05163314	PHASE3	TERMINATED	A Study of Soticlestat as an Add-on Therapy in Children and Adults With Dravet Syndrome or Lennox-Gastaut Syndrome
NCT05560282	PHASE3	TERMINATED	Fenfluramine for Adult Dravet Patients
NCT06118255	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Fenfluramine (Hydrochloride) in Infants 1 Year to Less Than 2 Years of Age With Dravet Syndrome
NCT06422377	PHASE3	TERMINATED	A Study Evaluating Soticlestat in Participants With Dravet Syndrome or Lennox-Gastaut Syndrome Who Have Been Exposed to Fenfluramine
NCT06660394	PHASE3	RECRUITING	A Phase 3, Placebo-Controlled Study to Investigate LP352 in Children and Adults With Dravet Syndrome (DS)
NCT06872125	PHASE3	RECRUITING	A Double-blind Study Evaluating the Efficacy, Safety, and Tolerability of Zorevunersen in Patients With Dravet Syndrome
NCT01254019	PHASE3	COMPLETED	A Clinical Study to Assess the Efficacy and Safety of GSK2402968 in Subjects With Duchenne Muscular Dystrophy
NCT01480245	PHASE3	TERMINATED	Open Label Study of GSK2402968 in Subjects With Duchenne Muscular Dystrophy
NCT01803412	PHASE3	TERMINATED	A Study of the Safety, Tolerability & Efficacy of Long-term Administration of Drisapersen in US & Canadian Subjects
NCT01826487	PHASE3	COMPLETED	Phase 3 Study of Ataluren in Participants With Nonsense Mutation Duchenne Muscular Dystrophy (nmDMD)
NCT01890798	PHASE3	WITHDRAWN	Drisapersen Duchenne Muscular Dystrophy (DMD) Treatment Protocol
NCT02090959	PHASE3	TERMINATED	An Extension Study of Ataluren (PTC124) in Participants With Nonsense Mutation Dystrophinopathy
NCT02432885	PHASE3	COMPLETED	Myocardial Fibrosis Progression in Duchenne and Becker Muscular Dystrophy - ACE Inhibitor Therapy Trial
NCT03179631	PHASE3	COMPLETED	Long-Term Outcomes of Ataluren in Duchenne Muscular Dystrophy
NCT05126758	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Deramiocel (CAP-1002) in Ambulatory and Non-Ambulatory Patients With Duchenne Muscular Dystrophy
NCT07587242	PHASE3	NOT_YET_RECRUITING	A Phase 3 Study to Evaluate the Safety and Efficacy of AOC 1044 (Also Referred to as Delpacibart Zotadirsen) in Participants With DMD With Gene Mutations Amenable to Exon 44 Skipping
NCT07608432	PHASE3	RECRUITING	Efficacy, Safety, and Tolerability of Zeleciment Rostudirsen (DYNE-251) Administered Intravenously Every 4 Weeks in Ambulatory Participants With Duchenne Muscular Dystrophy (FORZETTO)