PSMA4

Summary

PSMA4 (proteasome 20S subunit alpha 4, HGNC:9533) is a protein-coding gene on chromosome 15q25.1, encoding Proteasome subunit alpha type-4 (P25789). 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 99.7% of cancer cell lines).

This gene encodes a core alpha subunit of the 20S proteosome, which is a highly ordered ring-shaped structure composed of four rings of 28 non-identical subunits. Proteasomes cleave peptides in an ATP- and ubiquitin-dependent manner.

Source: NCBI Gene 5685 — RefSeq curated summary.

At a glance

• GWAS associations: 28
• Clinical variants (ClinVar): 24 total
• Druggable target: yes — 6 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 99.7% of screened cell lines (common-essential)
• MANE Select transcript: NM_002789

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9533
Approved symbol	PSMA4
Name	proteasome 20S subunit alpha 4
Location	15q25.1
Locus type	gene with protein product
Status	Approved
Aliases	HC9, HsT17706
Ensembl gene	ENSG00000041357
Ensembl biotype	protein_coding
OMIM	176846
Entrez	5685

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 24 protein_coding, 6 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000044462, ENST00000413382, ENST00000557929, ENST00000558094, ENST00000558281, ENST00000558341, ENST00000558635, ENST00000558639, ENST00000559082, ENST00000559146, ENST00000559154, ENST00000559365, ENST00000559437, ENST00000559906, ENST00000559934, ENST00000559948, ENST00000560033, ENST00000560099, ENST00000560217, ENST00000560737, ENST00000560842, ENST00000859802, ENST00000859803, ENST00000859804, ENST00000859805, ENST00000859806, ENST00000859807, ENST00000859808, ENST00000859809, ENST00000920050, ENST00000920051, ENST00000920052

RefSeq mRNA: 6 — MANE Select: NM_002789 NM_001102667, NM_001102668, NM_001330673, NM_001330675, NM_001330676, NM_002789

CCDS: CCDS10303, CCDS45319, CCDS86478, CCDS86479

Canonical transcript exons

ENST00000044462 — 9 exons

Exon	Start	End
ENSE00001814481	78548790	78552417
ENSE00002554217	78540444	78540539
ENSE00003473522	78544869	78544957
ENSE00003486880	78545634	78545764
ENSE00003526690	78542483	78542645
ENSE00003530356	78542177	78542219
ENSE00003643595	78544190	78544267
ENSE00003689695	78541905	78541930
ENSE00003785334	78546575	78546698

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 99.26.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 124.2519 / max 3944.4436, expressed in 1821 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
147912	122.2834	1821
147914	1.8685	1008
147913	0.1000	17

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	99.26	gold quality
mononuclear cell	CL:0000842	99.15	gold quality
leukocyte	CL:0000738	99.09	gold quality
visceral pleura	UBERON:0002401	99.03	gold quality
parietal pleura	UBERON:0002400	98.98	gold quality
pleura	UBERON:0000977	98.83	gold quality
ganglionic eminence	UBERON:0004023	98.82	gold quality
islet of Langerhans	UBERON:0000006	98.78	gold quality
rectum	UBERON:0001052	98.78	gold quality
ventricular zone	UBERON:0003053	98.75	gold quality
adrenal tissue	UBERON:0018303	98.58	gold quality
smooth muscle tissue	UBERON:0001135	98.57	gold quality
palpebral conjunctiva	UBERON:0001812	98.57	gold quality
left testis	UBERON:0004533	98.57	gold quality
right testis	UBERON:0004534	98.57	gold quality
esophagus squamous epithelium	UBERON:0006920	98.53	gold quality
vermiform appendix	UBERON:0001154	98.50	gold quality
tongue squamous epithelium	UBERON:0006919	98.50	gold quality
lymph node	UBERON:0000029	98.46	gold quality
granulocyte	CL:0000094	98.41	gold quality
calcaneal tendon	UBERON:0003701	98.41	gold quality
embryo	UBERON:0000922	98.35	gold quality
mucosa of transverse colon	UBERON:0004991	98.33	gold quality
epithelium of nasopharynx	UBERON:0001951	98.31	gold quality
nasopharynx	UBERON:0001728	98.29	gold quality
squamous epithelium	UBERON:0006914	98.28	gold quality
endometrium	UBERON:0001295	98.27	gold quality
gingival epithelium	UBERON:0001949	98.27	gold quality
gall bladder	UBERON:0002110	98.27	gold quality
right adrenal gland	UBERON:0001233	98.22	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-9067	yes	20.76
E-CURD-46	yes	19.46
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREM

miRNA regulators (miRDB)

25 targeting PSMA4, 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-6867-5P	100.00	82.21	3464
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-6757-3P	99.63	66.88	1089
HSA-MIR-6833-5P	99.50	68.93	1161
HSA-MIR-3911	99.38	66.95	1087
HSA-MIR-548V	99.29	69.47	1157
HSA-MIR-4758-3P	99.12	63.96	869
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-4520-3P	98.75	66.55	963
HSA-MIR-147A	98.33	66.40	795
HSA-MIR-5581-5P	97.91	66.50	965
HSA-MIR-10526-3P	97.86	64.97	1342
HSA-MIR-3614-3P	97.81	67.15	582
HSA-MIR-3190-3P	97.61	66.95	1406
HSA-MIR-3189-5P	97.55	66.71	655
HSA-MIR-5699-5P	97.36	67.03	1014
HSA-MIR-711	96.60	65.75	528
HSA-MIR-3169	96.40	67.58	698
HSA-MIR-208A-3P	95.87	66.51	397
HSA-MIR-208B-3P	95.87	66.56	396
HSA-MIR-7975	95.04	66.76	516
HSA-MIR-3130-3P	94.98	66.97	574

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.7% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 7)

• Unexpected interaction between alpha4 and alpha7 subunits may provide a molecular basis for the formation of previously reported 13S and 16S assembly intermediates. (PMID:15225636)
• Parkin interacts with the proteasome subunit alpha4 (PMID:15987638)
• study concludes polymorphisms of TGM5, PPAP2B and PSMA4 are not major contributors tonon-small cell lung cancer susceptibility in never-smoking hinese population, this primarily can be attributed to the significantly distinct genetic background of Asian populations from western populations (PMID:24518713)
• rs12901682 is associated with lung cancer risk in a Chinese Han population. (PMID:25744645)
• Five of these SNPs acted as cis-eQTLs, being associated with the transcription of IREB2 (rs2568494, rs16969968, rs11634351, rs6495309), PSMA4 (rs6495309) and ERCC1 (rs735482), out of 10,821 genes analyzed in lung. For these three genes, we obtained experimental evidence of differential allelic expression in lung tissue, pointing to the existence of in-cis genomic variants that regulate their transcription. (PMID:28181565)
• All four variants were significantly associated (P < 1.4 x 10(-6)) with blood DNA methylation of IREB2, CHRNA3 and PSMA4, of which two, including IREB2 and PSMA4, were also differentially methylated in Chronic obstructive pulmonary disease cases and controls (PMID:29422661)
• Potentially functional genetic variants of VAV2 and PSMA4 in the immune-activation pathway and non-small cell lung cancer survival. (PMID:36039727)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	psma4	ENSDARG00000045928
mus_musculus	Psma4	ENSMUSG00000032301
rattus_norvegicus	Psma4	ENSRNOG00000013493
drosophila_melanogaster	Prosalpha3	FBGN0261394
drosophila_melanogaster	Prosalpha3T	FBGN0261395
caenorhabditis_elegans	pas-3	WBGENE00003924

Paralogs (18): PSMB1 (ENSG00000008018), PSMA3 (ENSG00000100567), PSMB5 (ENSG00000100804), PSMA6 (ENSG00000100902), PSMA7 (ENSG00000101182), PSMA2 (ENSG00000106588), PSMB2 (ENSG00000126067), PSMA1 (ENSG00000129084), PSMB7 (ENSG00000136930), PSMB6 (ENSG00000142507), PSMA5 (ENSG00000143106), PSMA8 (ENSG00000154611), PSMB4 (ENSG00000159377), PSMB8 (ENSG00000204264), PSMB10 (ENSG00000205220), PSMB11 (ENSG00000222028), PSMB9 (ENSG00000240065), PSMB3 (ENSG00000277791)

Protein

Protein identifiers

Proteasome subunit alpha type-4 — P25789 (reviewed: P25789)

Alternative names: Macropain subunit C9, Multicatalytic endopeptidase complex subunit C9, Proteasome component C9, Proteasome subunit L, Proteasome subunit alpha-3

All UniProt accessions (11): P25789, H0YKS0, H0YKT8, H0YL69, H0YLC2, H0YLS6, H0YMA1, H0YMI6, H0YMV3, H0YMZ1, H0YN18

UniProt curated annotations — full annotation on UniProt →

Function. 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).

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. (Microbial infection) Interaction with HTLV-1 TAX protein favors NFKB1 activation.

Subcellular location. Cytoplasm. Nucleus.

Induction. Down-regulated by antioxidants BO-653 and probucol.

Similarity. Belongs to the peptidase T1A family.

Isoforms (2)

UniProt ID	Names	Canonical?
P25789-1	1	yes
P25789-2	2

RefSeq proteins (6): NP_001096137, NP_001096138, NP_001317602, NP_001317604, NP_001317605, NP_002780* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000426	Proteasome_asu_N	Domain
IPR001353	Proteasome_sua/b	Family
IPR016050	Proteasome_bsu_CS	Conserved_site
IPR023332	Proteasome_alpha-type	Family
IPR029055	Ntn_hydrolases_N	Homologous_superfamily
IPR050115	Proteasome_alpha	Family

Pfam: PF00227, PF10584

Enzyme classification (BRENDA):

• EC 3.4.25.1 — proteasome endopeptidase complex (BRENDA: 45 organisms, 202 substrates, 283 inhibitors, 33 Km, 33 kcat entries)

Substrate kinetics (BRENDA)

27 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
BENZYLOXYCARBONYL-GPAFG-4-AMINOBENZOATE	0.38–3.3	3
ACETYL-EPFD-7-AMIDO-4-CARBAMOYLCOUMARIN	0.032–0.088	2
ACETYL-NORLEUCINE-ARG-NORLEUCINE-ARG-7-AMIDO-4-C	0.11–0.67	2
ACETYL-YWTQ-7-AMIDO-4-CARBAMOYLCOUMARIN	0.027–0.038	2
BENZYLOXYCARBONYL-GPALG-4-AMINOBENZOATE	0.14–0.57	2
ABZ-VAL-VAL-SER-(4-GUANIDINO-PHE)-ALA-MET-GLY-TY	0.0042	1
ABZ-VAL-VAL-SER-ARG-SER-LEU-GLY-TYR(3-NO2)-NH2	0.0177	1
ACETYL-ARG-HSER-THR-ARG-7-AMIDO-4-METHYLCOUMARIN	0.0094	1
ACETYL-BETAALA-MET(SULFONE)-THR-ARG-7-AMIDO-4-ME	0.051	1
ACETYL-HARG-PRO-2-FLUORO-PHE-ASP-7-AMIDO-4-METHY	0.0159	1
ACETYL-HARG-PRO-ABU-ASP-7-AMIDO-4-METHYLCOUMARIN	0.0432	1
ACETYL-HHSL-7-AMIDO-4-CARBAMOYLCOUMARIN	0.36	1
BENZOYL-VGR-7-AMIDO-4-METHYLCOUMARIN	0.1	1
BENZYLOXYCARBONYL-ARR-7-AMIDO-4-METHYLCOUMARIN	0.248	1
BENZYLOXYCARBONYL-GGF-4-AMINOBENZOATE	2.29	1

UniProt features (36 total): strand 13, helix 8, turn 7, modified residue 5, chain 1, region of interest 1, splice variant 1

Structure

Experimental structures (PDB)

171 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
8QYL	ELECTRON MICROSCOPY	2.67
8CVR	ELECTRON MICROSCOPY	2.7
6KWY	ELECTRON MICROSCOPY	2.72
8QYJ	ELECTRON MICROSCOPY	2.73
8QYM	ELECTRON MICROSCOPY	2.73
8USB	ELECTRON MICROSCOPY	2.73
9MBP	ELECTRON MICROSCOPY	2.75
9PDL	ELECTRON MICROSCOPY	2.76
6E5B	X-RAY DIFFRACTION	2.77
7NAN	ELECTRON MICROSCOPY	2.8
8TM6	ELECTRON MICROSCOPY	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P25789-F1	93.17	0.84

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 (5): 13, 75, 127, 173, 176

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: 508 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, REACTOME_DNA_REPLICATION, REACTOME_SIGNALING_BY_NOTCH, MODULE_52, 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, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_10, REACTOME_INNATE_IMMUNE_SYSTEM, MORF_MBD4, TGCGCANK_UNKNOWN, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, KEGG_PROTEASOME

GO Biological Process (3): proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), ubiquitin-dependent protein catabolic process (GO:0006511), obsolete proteolysis involved in protein catabolic process (GO:0051603)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (12): proteasome complex (GO:0000502), P-body (GO:0000932), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), centriole (GO:0005814), cytosol (GO:0005829), proteasome core complex (GO:0005839), proteasome core complex, alpha-subunit complex (GO:0019773), extracellular exosome (GO:0070062), sperm midpiece (GO:0097225), sperm head-tail coupling apparatus (GO:0120212)

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
intracellular protein-containing complex	3
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
binding	1
endopeptidase complex	1
cytoplasmic ribonucleoprotein granule	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
microtubule organizing center	1
intracellular membraneless organelle	1
cytoplasm	1
proteasome complex	1
catalytic complex	1
proteasome core complex	1
extracellular vesicle	1
sperm flagellum	1

Protein interactions and networks

STRING

3824 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PSMA4	CHRNA5	P30532	945
PSMA4	CHRNA3	P32297	939
PSMA4	CHRNB4	P30926	938
PSMA4	PSMB1	P20618	921
PSMA4	PSMB3	P31147	890
PSMA4	PSMC3	P17980	889
PSMA4	POMP	Q9Y244	861
PSMA4	PSMB6	P28072	852
PSMA4	PSMB2	P31145	819
PSMA4	PSMB4	P28070	807
PSMA4	PSMB5	P28074	781
PSMA4	PSMA3	P25788	777
PSMA4	PSMB9	P28065	766
PSMA4	PSMB7	Q99436	744
PSMA4	PSMC5	P47210	727

IntAct

244 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
PSMA4	PSMA1	psi-mi:“MI:0915”(physical association)	0.920
PSMA4	PSMA2	psi-mi:“MI:0915”(physical association)	0.910
PSMA2	PSMA4	psi-mi:“MI:0915”(physical association)	0.910
PSMB7	PSMB1	psi-mi:“MI:0914”(association)	0.900
PSMA4	PSMA7	psi-mi:“MI:0915”(physical association)	0.880
PSMA7	PSMA4	psi-mi:“MI:0915”(physical association)	0.880
PSMA2	PSMA7	psi-mi:“MI:0914”(association)	0.850
UCHL5	PSMD11	psi-mi:“MI:0914”(association)	0.840

BioGRID (857): PSMA4 (Affinity Capture-MS), PSMA4 (Two-hybrid), IKZF1 (Two-hybrid), PSMA4 (Affinity Capture-MS), PSMA4 (Affinity Capture-MS), PSMA4 (Affinity Capture-MS), PSMA4 (Affinity Capture-MS), PSMA4 (Affinity Capture-MS), PSMA4 (Affinity Capture-MS), PSMA4 (Affinity Capture-MS), CCAR2 (Co-fractionation), ELP6 (Co-fractionation), EXOSC4 (Co-fractionation), EXOSC5 (Co-fractionation), PSMA3 (Co-fractionation)

ESM2 similar proteins: A2Y9X7, O14250, O16812, O23708, O23712, O23715, O24362, O42265, O44156, O59770, O73672, O81148, O82530, O96788, P0C8Y9, P0DKK3, P0DKK4, P17220, P18053, P18420, P21670, P24495, P25786, P25787, P25789, P32379, P34066, P34119, P40301, P49722, P52427, P52428, P90513, Q27488, Q3T0X5, Q3T0Y5, Q3ZCK9, Q4KM35, Q4R3H2, Q5REN2

Diamond homologs: A2Y9X7, A2YXU2, A2Z3I9, A3CW55, A4FZT6, A4YCU9, A5UJS2, A6URN9, A6VIP0, A7I9C7, A9A846, B0R2T2, B6YSH9, B8GEZ3, C3MQ43, C3MVG1, C3N5R0, C3NEC6, C3NHC6, C4KHD9, C5A2C2, C6A459, F4JJE5, O24030, O24616, O24733, O26782, O29760, O59219, O73672, O81148, O81149, O82530, P0C8Y9, P0DKK3, P0DKK4, P17220, P18053, P21670, P23638

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PSMA4	“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	13	95.2×	4e-23
Proteasome assembly	22	57.5×	8e-32
Regulation of activated PAK-2p34 by proteasome mediated degradation	16	57.1×	1e-23
Cross-presentation of soluble exogenous antigens (endosomes)	17	55.3×	2e-24
Vpu mediated degradation of CD4	16	54.5×	2e-23
Autodegradation of the E3 ubiquitin ligase COP1	16	54.5×	2e-23
Ubiquitin-dependent degradation of Cyclin D	16	54.5×	2e-23
FBXL7 down-regulates AURKA during mitotic entry and in early mitosis	17	54.1×	3e-24

GO biological processes:

GO term	Partners	Fold	FDR
proteasome-mediated ubiquitin-dependent protein catabolic process	24	12.7×	4e-17

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	11
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1000 predictions. Top by Δscore:

Variant	Effect	Δscore
15:78542175:A:AG	acceptor_gain	1.0000
15:78542176:G:GA	acceptor_gain	1.0000
15:78542176:GT:G	acceptor_gain	1.0000
15:78542176:GTCTC:G	acceptor_gain	1.0000
15:78542218:AG:A	donor_loss	1.0000
15:78542219:GG:G	donor_loss	1.0000
15:78542220:G:GA	donor_loss	1.0000
15:78542221:T:A	donor_loss	1.0000
15:78542608:G:GT	donor_gain	1.0000
15:78542644:GA:G	donor_gain	1.0000
15:78542646:G:GG	donor_gain	1.0000
15:78542650:G:GG	donor_gain	1.0000
15:78544866:TA:T	acceptor_loss	1.0000
15:78544867:AGGT:A	acceptor_loss	1.0000
15:78544868:G:C	acceptor_loss	1.0000
15:78544868:GGT:G	acceptor_gain	1.0000
15:78544928:A:AG	donor_gain	1.0000
15:78544953:TGGAG:T	donor_loss	1.0000
15:78544955:G:GT	donor_gain	1.0000
15:78544955:GAGG:G	donor_loss	1.0000
15:78544958:G:T	donor_loss	1.0000
15:78545626:T:A	acceptor_gain	1.0000
15:78545628:TTAAA:T	acceptor_loss	1.0000
15:78545629:TAAA:T	acceptor_loss	1.0000
15:78545630:A:AG	acceptor_gain	1.0000
15:78545630:AAAG:A	acceptor_gain	1.0000
15:78545630:AAAGG:A	acceptor_loss	1.0000
15:78545631:A:G	acceptor_gain	1.0000
15:78545632:A:G	acceptor_gain	1.0000
15:78545632:AG:A	acceptor_gain	1.0000

AlphaMissense

1709 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:78542189:G:C	D6H	1.000
15:78542207:T:A	F12I	1.000
15:78542207:T:C	F12L	1.000
15:78542207:T:G	F12V	1.000
15:78542208:T:C	F12S	1.000
15:78542208:T:G	F12C	1.000
15:78542209:T:A	F12L	1.000
15:78542209:T:G	F12L	1.000
15:78542219:G:A	G16S	1.000
15:78542219:G:C	G16R	1.000
15:78542219:G:T	G16C	1.000
15:78542483:G:A	G16D	1.000
15:78542483:G:T	G16V	1.000
15:78542485:C:A	R17S	1.000
15:78542486:G:C	R17P	1.000
15:78542489:T:C	L18S	1.000
15:78542496:A:C	Q20H	1.000
15:78542496:A:T	Q20H	1.000
15:78542500:G:A	E22K	1.000
15:78542501:A:T	E22V	1.000
15:78542503:T:C	Y23H	1.000
15:78542504:A:G	Y23C	1.000
15:78542506:G:C	A24P	1.000
15:78542507:C:A	A24D	1.000
15:78542515:G:C	A27P	1.000
15:78542538:T:G	C34W	1.000
15:78542542:G:A	G36R	1.000
15:78542542:G:C	G36R	1.000
15:78542543:G:A	G36E	1.000
15:78544212:G:C	G78R	1.000

dbSNP variants (sampled 300 via entrez): RS1000076421 (15:78539981 A>G), RS1000674273 (15:78540862 G>A,C), RS1000771959 (15:78550829 G>T), RS1000774740 (15:78547995 C>G,T), RS1001025077 (15:78541041 C>T), RS1001272041 (15:78547201 T>A,C), RS1001723229 (15:78546868 T>C), RS1002063314 (15:78541574 C>A,T), RS1002117056 (15:78541283 C>T), RS1002185577 (15:78551610 C>G,T), RS1002295601 (15:78546210 G>A), RS1002327600 (15:78548348 C>T), RS1002450806 (15:78546057 G>A), RS1003064398 (15:78543259 G>A), RS1003226975 (15:78549911 T>C)

Disease associations

OMIM: gene MIM:176846 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

28 associations (top):

Study	Trait	p-value
GCST000170_1	Lung cancer	5.000000e-20
GCST000172_1	Lung cancer	3.000000e-18
GCST000233_1	Lung cancer	1.000000e-08
GCST001476_19	Response to tocilizumab in rheumatoid arthritis	4.000000e-08
GCST002539_77	Schizophrenia	2.000000e-13
GCST002798_1	Pulmonary artery enlargement and chronic obstructive pulmonary disease	7.000000e-10
GCST003262_413	Post bronchodilator FEV1	3.000000e-09
GCST003262_442	Post bronchodilator FEV1	1.000000e-09
GCST003262_48	Post bronchodilator FEV1	6.000000e-07
GCST003262_641	Post bronchodilator FEV1	5.000000e-11
GCST003262_859	Post bronchodilator FEV1	4.000000e-09
GCST003262_934	Post bronchodilator FEV1	1.000000e-08
GCST003264_1238	Post bronchodilator FEV1/FVC ratio	3.000000e-07
GCST003264_1424	Post bronchodilator FEV1/FVC ratio	2.000000e-06
GCST003264_569	Post bronchodilator FEV1/FVC ratio	5.000000e-07
GCST003264_658	Post bronchodilator FEV1/FVC ratio	3.000000e-07
GCST003264_700	Post bronchodilator FEV1/FVC ratio	3.000000e-08
GCST003775_1	Lung cancer	1.000000e-09
GCST004521_146	Autism spectrum disorder or schizophrenia	2.000000e-08
GCST004521_223	Autism spectrum disorder or schizophrenia	5.000000e-10
GCST004521_293	Autism spectrum disorder or schizophrenia	5.000000e-08
GCST004946_128	Schizophrenia	2.000000e-10
GCST006803_32	Schizophrenia	3.000000e-12
GCST007637_9	Diffusing capacity of carbon monoxide	3.000000e-10
GCST011020_8	Intracranial aneurysm	1.000000e-09
GCST011021_13	Intracranial aneurysm	3.000000e-08
GCST011702_7	Smoking cessation	9.000000e-10
GCST012020_461	Serum metabolite levels	7.000000e-66

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0006347	pulmonary artery enlargement
EFO:0004314	forced expiratory volume
EFO:0004713	FEV/FVC ratio
EFO:0009369	diffusing capacity of the lung for carbon monoxide
EFO:0004319	smoking cessation

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2364701 (PROTEIN COMPLEX), CHEMBL3831201 (PROTEIN COMPLEX GROUP), CHEMBL6066933 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

6 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 43,258 (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
CHEMBL1232461	MOLIBRESIB	2	1,538

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs57064725	Metabolism/PK	3	cotinine	Tobacco Use Disorder

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs57064725	PSMA4	3	0.00	1	cotinine
rs880395	PSMA4		0.00	0

ChEMBL bioactivities

315 potent at pChembl≥5 of 341 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

282 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

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Arsenic	decreases expression, increases abundance, affects cotreatment, increases expression	3
bisphenol A	decreases expression	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Particulate Matter	increases abundance, decreases expression	2
aristolochic acid I	increases expression	1
FR900359	decreases phosphorylation	1
bisphenol F	increases expression	1
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
uranyl acetate	affects expression	1
arsenite	affects binding, increases reaction	1
nickel sulfate	decreases expression	1
epigallocatechin gallate	increases expression	1
arsenic trichloride	decreases expression, increases abundance	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	increases expression	1
CD 437	decreases expression	1
K 7174	decreases expression	1
poly(propyleneimine)	increases expression	1
3-(4’-hydroxy-3’-adamantylbiphenyl-4-yl)acrylic acid	decreases expression	1
bisphenol B	increases expression	1
bisphenol S	increases expression	1
picoxystrobin	increases expression	1
bisphenol AF	increases expression	1
Air Pollutants, Occupational	decreases expression	1
Vehicle Emissions	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Doxorubicin	increases metabolic processing	1
Environmental Pollutants	affects expression	1

ChEMBL screening assays

175 unique, capped per target: 166 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)

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