PSMC3

Summary

PSMC3 (proteasome 26S subunit, ATPase 3, HGNC:9549) is a protein-coding gene on chromosome 11p11.2, encoding 26S proteasome regulatory subunit 6A (P17980). Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. It is a common-essential gene (DepMap: required in 99.9% of cancer cell lines).

The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core 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. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase 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 one of the ATPase subunits, a member of the triple-A family of ATPases that have chaperone-like activity. This subunit may compete with PSMC2 for binding to the HIV tat protein to regulate the interaction between the viral protein and the transcription complex. A pseudogene has been identified on chromosome 9.

Source: NCBI Gene 5702 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 35
• Clinical variants (ClinVar): 76 total — 9 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 16
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 99.9% of screened cell lines (common-essential)
• MANE Select transcript: NM_002804

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9549
Approved symbol	PSMC3
Name	proteasome 26S subunit, ATPase 3
Location	11p11.2
Locus type	gene with protein product
Status	Approved
Aliases	TBP1, TBP-1, RPT5
Ensembl gene	ENSG00000165916
Ensembl biotype	protein_coding
OMIM	186852
Entrez	5702

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 16 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay

ENST00000298852, ENST00000524447, ENST00000526993, ENST00000527906, ENST00000528362, ENST00000529500, ENST00000530651, ENST00000530887, ENST00000530912, ENST00000531051, ENST00000531653, ENST00000602866, ENST00000619920, ENST00000876192, ENST00000876193, ENST00000936755, ENST00000936756, ENST00000936757, ENST00000936758, ENST00000970664, ENST00000970665

RefSeq mRNA: 1 — MANE Select: NM_002804 NM_002804

CCDS: CCDS7935

Canonical transcript exons

ENST00000298852 — 12 exons

Exon	Start	End
ENSE00001098085	47420264	47420409
ENSE00001098089	47420631	47420727
ENSE00001098090	47419116	47419197
ENSE00002194938	47426205	47426439
ENSE00003474104	47422830	47422973
ENSE00003554374	47425121	47425246
ENSE00003565119	47424607	47424711
ENSE00003606661	47424429	47424491
ENSE00003665701	47424046	47424183
ENSE00003671906	47425867	47425950
ENSE00003789798	47422574	47422722
ENSE00003910939	47418775	47418945

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 98.65.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 104.7869 / max 2637.0157, expressed in 1826 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
119613	88.0392	1826
119614	16.7476	1799

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	98.65	gold quality
gastrocnemius	UBERON:0001388	98.57	gold quality
muscle of leg	UBERON:0001383	98.48	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.35	gold quality
islet of Langerhans	UBERON:0000006	98.32	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.12	gold quality
lower esophagus	UBERON:0013473	98.11	gold quality
ganglionic eminence	UBERON:0004023	98.02	gold quality
popliteal artery	UBERON:0002250	98.01	gold quality
tibial artery	UBERON:0007610	98.01	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.95	gold quality
caudate nucleus	UBERON:0001873	97.90	gold quality
calcaneal tendon	UBERON:0003701	97.85	gold quality
right atrium auricular region	UBERON:0006631	97.81	gold quality
heart left ventricle	UBERON:0002084	97.80	gold quality
right frontal lobe	UBERON:0002810	97.79	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.76	gold quality
aorta	UBERON:0000947	97.70	gold quality
cingulate cortex	UBERON:0003027	97.68	gold quality
prefrontal cortex	UBERON:0000451	97.66	gold quality
monocyte	CL:0000576	97.64	gold quality
left coronary artery	UBERON:0001626	97.64	gold quality
anterior cingulate cortex	UBERON:0009835	97.64	gold quality
smooth muscle tissue	UBERON:0001135	97.60	gold quality
ventricular zone	UBERON:0003053	97.60	gold quality
rectum	UBERON:0001052	97.59	gold quality
cardiac ventricle	UBERON:0002082	97.59	gold quality
skin of leg	UBERON:0001511	97.57	gold quality
right coronary artery	UBERON:0001625	97.55	gold quality
putamen	UBERON:0001874	97.54	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ENAD-17	no	2531.77
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.9% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 13)

• role in E3 ubiquitin ligase function of the von Hippel-Lindau protein (PMID:14556007)
• molecular modeling of DNA:TATA element binding protein (TBP) interactions after treatment with 2-Chloro-2’-deoxyadenosine (PMID:14610662)
• Tat-binding protein-1 binds to human ARF tumor suppressor and has a role in control of cell proliferation (PMID:14665636)
• In normal cells, unmodified S12 associates with the 26S proteasome, while modified S12-M does not. (PMID:15221960)
• The stabilization effect exerted by TBP-1 requires an intact N-terminal 39 amino acids in ARF and occurs independently from N-terminal ubiquitination of the protein. (PMID:17334400)
• Heplipin induced KG-1 cell apoptosis is related with Wntl3 and ATPase3. (PMID:17649721)
• findings suggest that a component of 19S regulatory particles directly binds AR and might participate in AR-mediated transcriptional activation in cooperation with TBPIP. (PMID:19325002)
• 19S ATPase S6b (S6’/TBP1) binds CIITApIV in an S6a-dependent fashion and has effects similar to S6a on CIITApIV histone acetylation. (PMID:19853614)
• Circular circPSMC3 inhibits hepatocellular carcinoma migration and invasion by upregulating RBM5. (PMID:31726810)
• Circ PSMC3 inhibits prostate cancer cell proliferation by downregulating DGCR8. (PMID:32196577)
• CircPSMC3 Suppresses Migration and Invasion of Non-Small Cell Lung Cancer Cells via miR-182-5p/NME2 Axis. (PMID:32386284)
• Proteasome subunit PSMC3 variants cause neurosensory syndrome combining deafness and cataract due to proteotoxic stress. (PMID:32500975)
• PSMC3 proteasome subunit variants are associated with neurodevelopmental delay and type I interferon production. (PMID:37256937)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	psmc3	ENSDARG00000007141
mus_musculus	Psmc3	ENSMUSG00000002102
rattus_norvegicus	Psmc3	ENSRNOG00000011414
drosophila_melanogaster	Rpt5	FBGN0028684
caenorhabditis_elegans	rpt-5	WBGENE00004505

Paralogs (5): PSMC4 (ENSG00000013275), PSMC5 (ENSG00000087191), PSMC6 (ENSG00000100519), PSMC1 (ENSG00000100764), PSMC2 (ENSG00000161057)

Protein

Protein identifiers

26S proteasome regulatory subunit 6A — P17980 (reviewed: P17980)

Alternative names: 26S proteasome AAA-ATPase subunit RPT5, Proteasome 26S subunit ATPase 3, Proteasome subunit P50, Tat-binding protein 1

All UniProt accessions (10): A0A140VK42, E9PKD5, E9PLG2, E9PM69, E9PMD8, E9PMW0, E9PN50, E9PS45, P17980, R4GNH3

UniProt curated annotations — full annotation on UniProt →

Function. Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC3 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.

Subunit / interactions. Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC3 and few additional components. Interacts with PAAF1. (Microbial infection) Interacts with HIV-1 Tat.

Subcellular location. Cytoplasm. Nucleus.

Post-translational modifications. Sumoylated by UBE2I in response to MEKK1-mediated stimuli.

Disease relevance. Deafness, cataract, impaired intellectual development, and polyneuropathy (DCIDP) [MIM:619354] An autosomal recessive disease characterized by early onset of deafness, cataract, severe developmental delay, and severely impaired intellectual development. Patients later develop polyneuropathy of the lower extremities, associated with depigmentation of the hair in that area. The disease may be caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the AAA ATPase family.

RefSeq proteins (1): NP_002795* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003593	AAA+_ATPase	Domain
IPR003959	ATPase_AAA_core	Domain
IPR003960	ATPase_AAA_CS	Conserved_site
IPR012340	NA-bd_OB-fold	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR032501	Prot_ATP_ID_OB_2nd	Domain
IPR041569	AAA_lid_3	Domain
IPR050221	26S_Proteasome_ATPase	Family

Pfam: PF00004, PF16450, PF17862

UniProt features (43 total): helix 16, strand 14, turn 6, modified residue 3, sequence conflict 2, chain 1, binding site 1

Structure

Experimental structures (PDB)

130 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
9K53	ELECTRON MICROSCOPY	2.5
8USB	ELECTRON MICROSCOPY	2.73
9MBP	ELECTRON MICROSCOPY	2.75
9PDL	ELECTRON MICROSCOPY	2.76
9NKG	ELECTRON MICROSCOPY	2.8
9E8I	ELECTRON MICROSCOPY	2.87
9BV3	ELECTRON MICROSCOPY	2.9
9E8H	ELECTRON MICROSCOPY	2.9
9K4J	ELECTRON MICROSCOPY	2.9
9NKF	ELECTRON MICROSCOPY	2.9
9U3L	ELECTRON MICROSCOPY	2.91
9NKI	ELECTRON MICROSCOPY	2.94
9PDI	ELECTRON MICROSCOPY	2.98
6MSB	ELECTRON MICROSCOPY	3
7W37	ELECTRON MICROSCOPY	3
8CVT	ELECTRON MICROSCOPY	3
9E8G	ELECTRON MICROSCOPY	3.01
9PDN	ELECTRON MICROSCOPY	3.04
9MBQ	ELECTRON MICROSCOPY	3.08
7W38	ELECTRON MICROSCOPY	3.1
8USC	ELECTRON MICROSCOPY	3.1
9BV1	ELECTRON MICROSCOPY	3.1
9E8O	ELECTRON MICROSCOPY	3.1
9K4R	ELECTRON MICROSCOPY	3.1
9E8Q	ELECTRON MICROSCOPY	3.16
9U7R	ELECTRON MICROSCOPY	3.17
6MSD	ELECTRON MICROSCOPY	3.2
6MSK	ELECTRON MICROSCOPY	3.2
7W39	ELECTRON MICROSCOPY	3.2
7W3G	ELECTRON MICROSCOPY	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P17980-F1	80.58	0.25

Functional residue map

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

Ligand- & substrate-binding residues (1): 227–234

Post-translational modifications (3): 1, 9, 376

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: 391 (showing top): REACTOME_DNA_REPLICATION, REACTOME_SIGNALING_BY_NOTCH, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, REACTOME_APC_C_CDH1_MEDIATED_DEGRADATION_OF_CDC20_AND_OTHER_APC_C_CDH1_TARGETED_PROTEINS_IN_LATE_MITOSIS_EARLY_G1, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, WHITEHURST_PACLITAXEL_SENSITIVITY, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, KEGG_PROTEASOME, PAL_PRMT5_TARGETS_UP, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOCC_SECRETORY_GRANULE, REACTOME_SCF_SKP2_MEDIATED_DEGRADATION_OF_P27_P21

GO Biological Process (5): blastocyst development (GO:0001824), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), host-mediated perturbation of viral transcription (GO:0043921), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of proteasomal protein catabolic process (GO:1901800)

GO Molecular Function (6): ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), proteasome-activating activity (GO:0036402), identical protein binding (GO:0042802), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (12): proteasome complex (GO:0000502), P-body (GO:0000932), extracellular region (GO:0005576), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), proteasome regulatory particle, base subcomplex (GO:0008540), membrane (GO:0016020), proteasome accessory complex (GO:0022624), secretory granule lumen (GO:0034774), ficolin-1-rich granule lumen (GO:1904813), cytoplasm (GO:0005737)

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	5
proteasomal protein catabolic process	3
ATP-dependent activity	2
protein-containing complex	2
intracellular anatomical structure	2
in utero embryonic development	1
anatomical structure development	1
ubiquitin-dependent protein catabolic process	1
host-mediated perturbation of viral process	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
positive regulation of protein catabolic process	1
regulation of proteasomal protein catabolic process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
polypeptide conformation or assembly isomerase activity	1
protein binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
intracellular protein-containing complex	1
endopeptidase complex	1
cytoplasmic ribonucleoprotein granule	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1
proteasome regulatory particle	1
proteasome complex	1
secretory granule	1
cytoplasmic vesicle lumen	1
intracellular organelle lumen	1
ficolin-1-rich granule	1

Protein interactions and networks

STRING

3590 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PSMC3	PSMD1	Q99460	896
PSMC3	PSMA4	P25789	889
PSMC3	PSMD2	Q13200	867
PSMC3	PSMC4	P43686	830
PSMC3	PSMA5	P28066	825
PSMC3	PSMB1	P20618	824
PSMC3	PSMA1	P25786	821
PSMC3	PSMA3	P25788	813
PSMC3	PSMB5	P28074	788
PSMC3	PSMD13	Q9UNM6	787
PSMC3	PSMD11	O00231	783
PSMC3	PSMD3	O43242	783
PSMC3	PSMD4	P55036	783
PSMC3	PSMC6	P49719	783
PSMC3	PSMB3	P31147	778

IntAct

336 interactions, top by confidence:

A	B	Type	Score
PSMC3	PSMC6	psi-mi:“MI:0915”(physical association)	0.950
PSMC6	PSMC3	psi-mi:“MI:0915”(physical association)	0.950
PSMC6	PSMC3	psi-mi:“MI:0407”(direct interaction)	0.950
PSMC3	PSMC6	psi-mi:“MI:0407”(direct interaction)	0.950
PSMC6	PSMC3	psi-mi:“MI:0914”(association)	0.950
PSMC3	PSMD9	psi-mi:“MI:0915”(physical association)	0.940
PSMD9	PSMC3	psi-mi:“MI:0915”(physical association)	0.940
PSMD9	PSMC3	psi-mi:“MI:0914”(association)	0.940
PSMC3	PSMD9	psi-mi:“MI:0407”(direct interaction)	0.940
UCHL5	PSMD11	psi-mi:“MI:0914”(association)	0.840
PSMD10	PSMD11	psi-mi:“MI:0914”(association)	0.800
PSMC3	TRAF4	psi-mi:“MI:0915”(physical association)	0.800
PSMC5	PSMC3	psi-mi:“MI:0914”(association)	0.760
PSMC6	PSMD10	psi-mi:“MI:0914”(association)	0.740

BioGRID (917): PSMC3 (Affinity Capture-MS), PSMC3 (Two-hybrid), PSMC6 (Two-hybrid), PSMD9 (Two-hybrid), KDM1A (Two-hybrid), AMOTL2 (Two-hybrid), PSMA2 (Reconstituted Complex), PSMC3 (Affinity Capture-RNA), PSMC3 (Affinity Capture-RNA), PSMC3 (Affinity Capture-RNA), PSMC3 (Biochemical Activity), UBC (Reconstituted Complex), PSMC3 (Affinity Capture-Western), PSMC3 (Affinity Capture-MS), PSMC3 (Affinity Capture-MS)

ESM2 similar proteins: A0JMA9, A8QFF6, A8XV40, A9RA82, B3EX35, B4USW8, B5X3X5, B7NZ88, O04019, O14126, O14325, O17071, O23894, O42587, O75449, P17980, P32795, P33297, P33298, P34123, P34808, P46465, P46470, P46502, P46508, P54776, P78578, P85200, Q07844, Q0IIR9, Q1HGK7, Q21222, Q3B8D5, Q4R407, Q54PN7, Q55BV5, Q5RII9, Q5U3S1, Q5XIK7, Q63569

Diamond homologs: A3CV35, A4G0S4, A6UQT3, A6VHR1, A7I8B8, A9A916, B6YXR2, B8GGN4, C3MRF1, C3MY47, C3MZI6, C3N7K8, C3NFW6, C4KIR6, C5A6P8, D4GUJ7, O04019, O16368, O17071, O18413, O23894, O26824, O28303, O42586, O42587, O57940, O74445, O76371, O88685, P17980, P33297, P34123, P34124, P36612, P40327, P41836, P43686, P46465, P46466, P46470

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PSMC3	“form complex”	“26S Proteasome”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 117 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
Regulation of activated PAK-2p34 by proteasome mediated degradation	16	53.7×	2e-22
Proteasome assembly	21	51.6×	6e-29
Vpu mediated degradation of CD4	16	51.2×	2e-22
Autodegradation of the E3 ubiquitin ligase COP1	16	51.2×	2e-22
Ubiquitin-dependent degradation of Cyclin D	16	51.2×	2e-22
Regulation of ornithine decarboxylase (ODC)	15	49.1×	4e-21
Cross-presentation of soluble exogenous antigens (endosomes)	16	48.9×	4e-22
Vif-mediated degradation of APOBEC3G	16	48.9×	4e-22

GO biological processes:

GO term	Partners	Fold	FDR
proteasome-mediated ubiquitin-dependent protein catabolic process	22	11.7×	1e-14
ubiquitin-dependent protein catabolic process	8	6.1×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	2
Uncertain significance	36
Likely benign	9
Benign	0

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
1804031	NM_002804.5(PSMC3):c.910C>T (p.Arg304Trp)	Pathogenic
3363101	NM_002804.5(PSMC3):c.910C>G (p.Arg304Gly)	Pathogenic
3376864	NM_002804.5(PSMC3):c.777G>A (p.Met259Ile)	Pathogenic
4813651	NM_002804.5(PSMC3):c.784G>A (p.Gly262Arg)	Pathogenic
4813652	NM_002804.5(PSMC3):c.915G>T (p.Glu305Asp)	Pathogenic
4813653	NM_002804.5(PSMC3):c.1147G>A (p.Glu383Lys)	Pathogenic
4813654	NM_002804.5(PSMC3):c.710C>T (p.Ala237Val)	Pathogenic
4813655	NM_002804.5(PSMC3):c.775A>G (p.Met259Val)	Pathogenic
599398	NM_002804.5(PSMC3):c.1127+337A>G	Pathogenic
2205821	NM_002804.5(PSMC3):c.929T>C (p.Met310Thr)	Likely pathogenic
3377190	NM_002804.5(PSMC3):c.464A>G (p.Lys155Arg)	Likely pathogenic

SpliceAI

1652 predictions. Top by Δscore:

Variant	Effect	Δscore
11:47419193:CAGGA:C	acceptor_gain	1.0000
11:47419194:AGGA:A	acceptor_gain	1.0000
11:47419195:GGA:G	acceptor_gain	1.0000
11:47419196:GA:G	acceptor_gain	1.0000
11:47419197:ACTG:A	acceptor_loss	1.0000
11:47419198:C:CC	acceptor_gain	1.0000
11:47419198:CTG:C	acceptor_loss	1.0000
11:47419199:T:C	acceptor_loss	1.0000
11:47419205:C:CT	acceptor_gain	1.0000
11:47419206:A:T	acceptor_gain	1.0000
11:47420259:CTCA:C	donor_loss	1.0000
11:47420261:CA:C	donor_loss	1.0000
11:47420262:A:AC	donor_gain	1.0000
11:47420262:A:C	donor_loss	1.0000
11:47420263:C:CC	donor_gain	1.0000
11:47420263:C:CG	donor_loss	1.0000
11:47420263:CCTGA:C	donor_gain	1.0000
11:47420405:ATTAC:A	acceptor_gain	1.0000
11:47420406:TTAC:T	acceptor_gain	1.0000
11:47420407:TAC:T	acceptor_gain	1.0000
11:47420408:AC:A	acceptor_gain	1.0000
11:47420409:CC:C	acceptor_gain	1.0000
11:47420627:TCA:T	donor_loss	1.0000
11:47420628:CA:C	donor_loss	1.0000
11:47420629:A:AC	donor_gain	1.0000
11:47420629:AC:A	donor_gain	1.0000
11:47420630:C:CG	donor_gain	1.0000
11:47420630:CC:C	donor_gain	1.0000
11:47420630:CCTT:C	donor_gain	1.0000
11:47420630:CCTTA:C	donor_gain	1.0000

AlphaMissense

2905 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:47418888:C:G	G423R	1.000
11:47418944:C:T	G404D	1.000
11:47419133:C:G	A398P	1.000
11:47419147:C:T	G393E	1.000
11:47419148:C:A	G393W	1.000
11:47419148:C:G	G393R	1.000
11:47419148:C:T	G393R	1.000
11:47420283:A:G	S370P	1.000
11:47420342:C:G	R350P	1.000
11:47420345:T:A	D349V	1.000
11:47420346:C:G	D349H	1.000
11:47420351:C:A	R347L	1.000
11:47420351:C:G	R347P	1.000
11:47420351:C:T	R347H	1.000
11:47420352:G:A	R347C	1.000
11:47420352:G:C	R347G	1.000
11:47420352:G:T	R347S	1.000
11:47420354:C:A	G346V	1.000
11:47420354:C:T	G346D	1.000
11:47420355:C:A	G346C	1.000
11:47420355:C:G	G346R	1.000
11:47420360:C:G	R344P	1.000
11:47420361:G:A	R344C	1.000
11:47420361:G:T	R344S	1.000
11:47420363:A:G	L343P	1.000
11:47420366:A:C	L342R	1.000
11:47420366:A:G	L342P	1.000
11:47420366:A:T	L342H	1.000
11:47420369:G:A	A341V	1.000
11:47420369:G:T	A341D	1.000

dbSNP variants (sampled 300 via entrez): RS1000107979 (11:47426312 G>A), RS1000567223 (11:47421798 G>A,T), RS1000907217 (11:47426471 C>T), RS1000932226 (11:47419608 C>T), RS1000959229 (11:47426626 G>C,T), RS1001185284 (11:47423175 G>A), RS1001225780 (11:47419159 T>C,G), RS1001382949 (11:47419717 G>A), RS1001559799 (11:47419953 G>A), RS1001778455 (11:47424329 A>G,T), RS1001914055 (11:47427696 C>T), RS1001965177 (11:47427948 C>G), RS1002201129 (11:47422949 T>A,C), RS1002799121 (11:47424264 G>A), RS1003675559 (11:47421463 C>T)

Disease associations

OMIM: gene MIM:186852 | disease phenotypes: MIM:616326, MIM:208150, MIM:142700, MIM:607411, MIM:619354

GenCC curated gene-disease

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Strong	Autosomal dominant
neurodevelopmental disorder	Strong	Autosomal dominant
deafness, cataract, impaired intellectual development, and polyneuropathy	Moderate	Autosomal recessive

Mondo (12): congenital myasthenic syndrome 11 (MONDO:0014588), fetal akinesia deformation sequence 1 (MONDO:0100101), polymicrogyria (MONDO:0000087), developmental dysplasia of the hip (MONDO:0000158), microcephaly (MONDO:0001149), patent ductus arteriosus (MONDO:0011827), congenital pulmonary veins anomaly (MONDO:0020295), atrial septal defect, ostium secundum type (MONDO:0020434), patent foramen ovale (MONDO:0020439), neurodevelopmental disorder (MONDO:0700092), deafness, cataract, impaired intellectual development, and polyneuropathy (MONDO:0859159), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (8): Congenital myasthenic syndrome (Orphanet:590), Fetal akinesia deformation sequence (Orphanet:994), Polymicrogyria (Orphanet:35981), Congenital pulmonary veins anomaly (Orphanet:98729), Atrial septal defect, ostium secundum type (Orphanet:99103), Familial patent arterial duct (Orphanet:466729), NON RARE IN EUROPE: Patent arterial duct (Orphanet:706), NON RARE IN EUROPE: Patent foramen ovale (Orphanet:99108)

HPO phenotypes

16 total (18 of 16 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000272	Malar flattening
HP:0000322	Short philtrum
HP:0000336	Prominent supraorbital ridges
HP:0000365	Hearing impairment
HP:0000486	Strabismus
HP:0000519	Developmental cataract
HP:0000664	Synophrys
HP:0000729	Autistic behavior
HP:0001271	Polyneuropathy
HP:0003577	Congenital onset
HP:0007618	Subcutaneous calcification
HP:0009938	Sunken cheeks
HP:0011343	Moderate global developmental delay
HP:0011344	Severe global developmental delay
HP:0100830	Round ear
HP:0000252	Microcephaly
HP:0001655	Patent foramen ovale

GWAS associations

35 associations (top):

Study	Trait	p-value
GCST001699_12	Serum albumin levels	1.000000e-07
GCST001699_3	Serum albumin levels	8.000000e-08
GCST001956_37	Height	2.000000e-09
GCST004776_59	Systolic blood pressure	3.000000e-07
GCST004777_25	Diastolic blood pressure	7.000000e-08
GCST005170_27	Intraocular pressure	1.000000e-19
GCST005232_56	Neuroticism	1.000000e-16
GCST005580_146	Intraocular pressure	6.000000e-30
GCST005905_14	Global electrical heterogeneity phenotypes	6.000000e-09
GCST005973_42	White blood cell count	9.000000e-09
GCST006258_12	Diastolic blood pressure	9.000000e-19
GCST006259_19	Systolic blood pressure	4.000000e-13
GCST006716_13	Alcohol use disorder (total score)	6.000000e-09
GCST006923_11	Loneliness	1.000000e-07
GCST006924_13	Loneliness (MTAG)	1.000000e-08
GCST007293_118	Body fat distribution (arm fat ratio)	3.000000e-08
GCST007293_19	Body fat distribution (arm fat ratio)	2.000000e-10
GCST007293_45	Body fat distribution (arm fat ratio)	5.000000e-14
GCST007294_28	Body fat distribution (trunk fat ratio)	6.000000e-09
GCST007294_9	Body fat distribution (trunk fat ratio)	4.000000e-06
GCST007295_159	Body fat distribution (leg fat ratio)	1.000000e-18
GCST007295_24	Body fat distribution (leg fat ratio)	7.000000e-08
GCST007295_50	Body fat distribution (leg fat ratio)	2.000000e-12
GCST007388_49	Insomnia symptoms (never/rarely vs. usually)	2.000000e-09
GCST007559_27	Sleep duration (short sleep)	4.000000e-08
GCST007825_4	Alzheimer’s disease or fasting glucose levels (pleiotropy)	3.000000e-16
GCST007932_55	Medication use (thyroid preparations)	3.000000e-08
GCST008839_605	Height	7.000000e-30
GCST009685_31	Hypertension	5.000000e-13
GCST010002_238	Refractive error	2.000000e-14

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0006336	diastolic blood pressure
EFO:0004695	intraocular pressure measurement
EFO:0007660	neuroticism measurement
EFO:0004327	electrocardiography
EFO:0009458	alcohol use disorder measurement
EFO:0007865	loneliness measurement
EFO:0004341	body fat distribution
EFO:0007876	insomnia measurement
EFO:0009933	Thyroid preparation use measurement
EFO:0008111	diet measurement
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D000082602	Developmental Dysplasia of the Hip	C05.550.518.384.500; C05.660.297; C16.131.621.297
D004374	Ductus Arteriosus, Patent	C14.240.400.340; C14.280.400.340; C16.131.240.400.340
D054092	Foramen Ovale, Patent	C14.240.400.560.375.258; C14.280.400.560.375.258; C16.131.240.400.560.375.258
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D065886	Neurodevelopmental Disorders	F03.625
D065706	Polymicrogyria	C10.500.507.500.500; C16.131.666.507.500.500
C563831	Myasthenic Syndrome, Congenital, Ie (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2364701 (PROTEIN COMPLEX), CHEMBL3831207 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 25,628 (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

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

ChEMBL bioactivities

66 potent at pChembl≥5 of 67 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.62	IC50	2.4	nM	BORTEZOMIB
8.59	IC50	2.56	nM	BORTEZOMIB
8.57	IC50	2.7	nM	CHEMBL3237863
8.47	IC50	3.4	nM	CHEMBL6143686
8.41	IC50	3.9	nM	CHEMBL3237862
8.39	IC50	4.1	nM	CHEMBL3237864
8.39	IC50	4.1	nM	CHEMBL3237867
8.32	IC50	4.8	nM	CHEMBL3237873
8.30	Kd	4.973	nM	CHEMBL5653589
8.30	ED50	4.973	nM	CHEMBL5653589
8.29	IC50	5.1	nM	CHEMBL3237865
8.24	IC50	5.7	nM	CHEMBL3237866
8.24	IC50	5.7	nM	CHEMBL3237860
8.23	IC50	5.9	nM	CHEMBL3237868
8.15	IC50	7	nM	BORTEZOMIB
8.15	IC50	7.1	nM	CHEMBL3237870
8.15	IC50	7.14	nM	BORTEZOMIB
8.12	IC50	7.5	nM	CHEMBL3237871
8.11	IC50	7.7	nM	CHEMBL3237874
8.11	IC50	7.8	nM	CHEMBL3237869
8.07	IC50	8.6	nM	CARFILZOMIB
7.54	IC50	29	nM	CHEMBL3237861
7.34	IC50	46	nM	CHEMBL3237867
7.27	IC50	54	nM	CHEMBL3237872
7.12	IC50	75	nM	CHEMBL3237865
7.12	IC50	76	nM	CHEMBL3237866
6.96	IC50	110	nM	CHEMBL3262766
6.92	IC50	120	nM	CHEMBL3237864
6.92	IC50	120	nM	BORTEZOMIB
6.89	IC50	130	nM	CHEMBL3237869
6.85	IC50	140	nM	CHEMBL3237862
6.82	IC50	150	nM	CHEMBL3237863
6.77	IC50	170	nM	CHEMBL3237873
6.77	IC50	170	nM	CHEMBL3262765
6.72	IC50	190	nM	CHEMBL3262758
6.68	IC50	210	nM	CHEMBL3237870
6.66	IC50	220	nM	CHEMBL3262756
6.60	IC50	250	nM	CHEMBL3237868
6.47	IC50	340	nM	CHEMBL3262752
6.47	IC50	340	nM	CHEMBL3262755
6.44	IC50	360	nM	CHEMBL3262757
6.42	IC50	380	nM	CHEMBL3262754
6.36	IC50	440	nM	CHEMBL3262753
6.30	IC50	500	nM	CHEMBL3237872
6.20	IC50	630	nM	CHEMBL3262762
6.02	IC50	950	nM	CHEMBL3262761
6.00	IC50	1000	nM	CHEMBL3237871
5.96	IC50	1100	nM	CHEMBL3237862
5.85	IC50	1400	nM	BELACTOSIN A
5.84	IC50	1440	nM	BELACTOSIN A

PubChem BioAssay actives

62 with measured affinity, of 137 total; 34 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
Bortezomib	1985684: Inhibition of 26S proteasome (unknown origin)	ic50	0.0024	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
(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
(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-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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149117: Binding affinity to human PSMC3 incubated for 45 mins by Kinobead based pull down assay	kd	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)-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
(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
(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-[(6-phenylpyridine-2-carbonyl)amino]butanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0075	uM
[(1R)-1-[[(2S)-2-acetamido-4-oxo-4-[[3-phenylmethoxy-2-(phenylmethoxymethyl)propyl]amino]butanoyl]amino]-3-methylbutyl]boronic acid	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0077	uM
(2S)-2-benzamido-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	0.0078	uM
Carfilzomib	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.0086	uM
(2R,3S)-3-[(2S)-butan-2-yl]-4-oxo-N-[4-phenylmethoxy-3-(phenylmethoxymethyl)butyl]oxetane-2-carboxamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0290	uM
(2S)-2-acetamido-N’-methyl-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]butanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0540	uM
N-[(1R)-3-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-oxo-1-phenylpropyl]naphthalene-2-carboxamide	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.1100	uM
N-[(1R)-3-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-oxo-1-phenylpropyl]-4-(trifluoromethyl)benzamide	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.1700	uM
N-[3-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-oxo-1-phenylpropyl]naphthalene-2-carboxamide	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.1900	uM
N-[3-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-oxo-1-phenylpropyl]-4-(trifluoromethyl)benzamide	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.2200	uM
N-[3-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-oxo-1-phenylpropyl]pyridine-3-carboxamide	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.3400	uM
4-methoxy-N-[3-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-oxo-1-phenylpropyl]benzamide	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.3400	uM
4-cyano-N-[3-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-oxo-1-phenylpropyl]benzamide	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.3600	uM
4-fluoro-N-[3-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-oxo-1-phenylpropyl]benzamide	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.3800	uM
N-[3-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-oxo-1-phenylpropyl]benzamide	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.4400	uM
N-[3-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-oxo-1-phenylpropyl]oxane-4-carboxamide	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.6300	uM
N-[3-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-oxo-1-phenylpropyl]thiophene-2-carboxamide	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.9500	uM
(2S)-2-[[(2S)-2-aminopropanoyl]amino]-3-[(1S,2S)-2-[[(2R,3S)-3-[(2S)-butan-2-yl]-4-oxooxetane-2-carbonyl]amino]cyclopropyl]propanoic acid	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	1.4000	uM
(2S)-2-acetamido-N-[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]-N’-[4-phenylmethoxy-3-(phenylmethoxymethyl)butyl]butanediamide	1152964: Inhibition of chymotrypsin-like of human 20S proteasome using chromophoric Suc-LLVY-AMC as substrate after 60 mins by fluorescence assay	ic50	2.3000	uM
N-[3-(2-oxo-1,3,4-oxathiazol-5-yl)phenyl]acetamide	1137840: Inhibition of chymotrypsin-like activity of 26S proteasome in intact human Karpas 1106p cells assessed as substrate hydrolysis using Suc-LLVY-(D)-aminoluciferin as substrate after 3 hrs by cell-based Proteasome-Glo assay	ec50	4.2000	uM
(2S)-2-acetamido-N-[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]-N’-(4-phenylmethoxybutyl)butanediamide	1152964: Inhibition of chymotrypsin-like of human 20S proteasome using chromophoric Suc-LLVY-AMC as substrate after 60 mins by fluorescence assay	ic50	5.7000	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149117: Binding affinity to human PSMC3 incubated for 45 mins by Kinobead based pull down assay	kd	7.6246	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression	2
sodium arsenite	increases expression	2
Resveratrol	affects cotreatment, increases expression	2
Arsenic Trioxide	affects binding, decreases reaction, increases expression	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Benzo(a)pyrene	affects cotreatment, decreases expression, affects methylation	2
Smoke	decreases expression, increases abundance, increases expression	2
Tretinoin	affects cotreatment, increases expression, decreases expression	2
Cyclosporine	increases expression	2
Cadmium Chloride	decreases reaction, increases abundance, increases palmitoylation, decreases expression	2
FR900359	increases phosphorylation	1
TAK-243	decreases sumoylation	1
pirinixic acid	affects binding, decreases expression, increases activity	1
beta-lapachone	increases expression	1
cobaltous chloride	decreases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
perfluorooctanoic acid	decreases expression	1
manganese chloride	decreases expression, increases abundance	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	increases expression, affects cotreatment	1
coumarin	increases phosphorylation	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
phenethyl isothiocyanate	affects binding	1
di-n-butylphosphoric acid	affects expression	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	increases expression	1
bisphenol B	increases expression	1
14-deoxy-11,12-didehydroandrographolide	decreases expression	1
2-amino-14,16-dimethyloctadecan-3-ol	decreases expression	1
bisphenol S	affects expression	1
bisphenol AF	increases expression	1
Temozolomide	increases expression	1

ChEMBL screening assays

27 unique, capped per target: 27 binding

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

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00208364	PHASE4	TERMINATED	A Two Centre Study to Assess the Long-term Performance of the Pinnacle™ Cup With a Metal-on-Metal Bearing in Primary Total Hip Replacement
NCT00208377	PHASE4	TERMINATED	A Multi-centre Study to Assess the Long-term Performance of the DePuy ASR™ System in Primary Hip Resurfacing Surgery
NCT00208390	PHASE4	TERMINATED	A Multi-centre Study to Assess the Long-term Performance of the Summit™ Hip in Primary Total Hip Replacement
NCT00208429	PHASE4	WITHDRAWN	A Multi-centre Study to Assess the Long-term Performance of the Pinnacle™ Cup With a Polyethylene-on-metal Bearing in Primary Total Hip Replacement
NCT00208442	PHASE4	COMPLETED	A Randomised Single Centre Study to Compare the Long-term Wear Characteristics of Marathon™ and Enduron™ Polyethylene Cup Liners in Primary Total Hip Replacement
NCT00208455	PHASE4	TERMINATED	A Multi-centre Study to Assess the Long-term Performance of the DePuy PROXIMA™ Hip in Primary Total Hip Replacement
NCT00546598	PHASE4	TERMINATED	Post-approval Study of the DURALOC® Option Ceramic-on-Ceramic Hip Prosthesis System
NCT00715026	PHASE4	TERMINATED	Trilogy AB Acetabular Hip System Post Approval Study
NCT00872066	PHASE4	COMPLETED	A Study to Assess the Long-term Performance of SmartSet® HV and SmartSet® GHV Bone Cements in Primary Total Hip Replacement
NCT00872222	PHASE4	TERMINATED	A Single Centre Study to Assess the Long-term Performance of the Pinnacle™ Cup With a Ceramic-on-ceramic Bearing in Primary Total Hip Replacement
NCT00872547	PHASE4	TERMINATED	Multi-Centre Study to Assess the Long-term Performance of the DePuy ASR™ System in Resurfacing and Primary Total Hip Replacement
NCT00872573	PHASE4	TERMINATED	A Two Centre Study to Assess the Stability and Long-term Performance of the C-Stem™ AMT in a Total Primary Hip Replacement
NCT00872794	PHASE4	TERMINATED	A Single Centre Study to Assess the Long-term Performance of the DePuy ASR™ System in Primary Hip Resurfacing Surgery
NCT00873444	PHASE4	TERMINATED	A Randomised Study to Compare Metal Ion Release and Long-term Performance of the Pinnacle™ Cup With a Ceramic-on-Metal or a Metal-on-Metal Bearing
NCT01134445	PHASE4	TERMINATED	An Electronic Data Capture Study to Assess the Long-term Performance of the DePuy PROXIMA™ Hip in Primary Total Hip Replacement
NCT01422564	PHASE4	TERMINATED	Metal on Metal Versus Metal on Highly Crossed Linked Polyethylene Sytem
NCT01635166	PHASE4	TERMINATED	Multi-centre Study to Assess the Long-term Performance of the Deltamotion Cup System in Primary Hip Replacement Surgery
NCT00217191	PHASE4	COMPLETED	Ibuprofen and Renal Function in Premature Infants
NCT00642330	PHASE4	COMPLETED	Comparative Study of Efficacy and Safety of Oral Ibuprofen and Intravenous Ibuprofen in Closure of Patent Ductus Arteriosus in Very Low Birth Weight Infants
NCT00767039	PHASE4	TERMINATED	Curosurf and Survanta Treatment(CAST)of RDS in Very Premature Infants
NCT00961753	PHASE4	TERMINATED	Safety/Efficacy Study of Optimizing Ibuprofen Dosing to Achieve Higher PDA Closure Rates
NCT01536158	PHASE4	COMPLETED	Oral Paracetamol Versus Oral Ibuprofen in Management of Patent Ductus Arteriosus in Preterm Infants: A Randomised Controlled Trial
NCT01544972	PHASE4	UNKNOWN	Serum Level Measurement of Oral Paracetamol and Oral Ibuprofen for Patent Ductus Arteriosus Treatment in Preterm Infants
NCT03265782	PHASE4	UNKNOWN	Paracetamol Versus Ibuprofen for PDA Closure
NCT00697151	PHASE4	COMPLETED	Patent Foramen Ovale in Cryptogenic Stroke Study
NCT01550588	PHASE4	UNKNOWN	Device Closure Versus Medical Therapy for Cryptogenic Stroke Patients With High-Risk Patent Foramen Ovale (DEFENSE-PFO)
NCT05561660	PHASE4	UNKNOWN	COMParison of the EffecT of dEvice Closure in Alleviating Migraine With PFO (COMPETE-2)
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT00208351	PHASE3	TERMINATED	A Randomised Single Centre Study to Compare the Long-term Performance of 4 Designs of the DePuy Ultima LX Stem in Primary Total Hip Replacement
NCT00208468	PHASE3	TERMINATED	A Randomised Multi-centre Study to Compare the Long-term Performance of the Future Hip to 3 Other Implants in Primary Total Hip Replacement
NCT00440804	PHASE3	COMPLETED	Safety and Efficacy Study of Ibuprofen l-Lysine Solution in Premature Infants for Treatment of PDA
NCT00485160	PHASE3	COMPLETED	Ibuprofen vs. Continuous Indomethacin in the Treatment of PDA
NCT01593163	PHASE3	COMPLETED	Echocardiographically Guided Versus Standard Ibuprofen Treatment for Patent Ductus Arteriosus
NCT01630278	PHASE3	COMPLETED	Early Ibuprofen Treatment of Patent Ductus Arteriosus (PDA) in Premature Infants (TRIOCAPI)
NCT01755728	PHASE3	COMPLETED	Paracetamol (Acetaminophen) for Closure of PDA in Preterm Infants