SEM1

Summary

SEM1 (SEM1 26S proteasome subunit, HGNC:10845) is a protein-coding gene on chromosome 7q21.3, encoding 26S proteasome complex subunit SEM1 (P60896). 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 98.0% of cancer cell lines).

The product of this gene has been localized within the split hand/split foot malformation locus SHFM1 at chromosome 7. It has been proposed to be a candidate gene for the autosomal dominant form of the heterogeneous limb developmental disorder split hand/split foot malformation type 1. In addition, it has been shown to directly interact with BRCA2. It also may play a role in the completion of the cell cycle.

Source: NCBI Gene 7979 — RefSeq curated summary.

At a glance

• GWAS associations: 35
• Clinical variants (ClinVar): 11 total — 2 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 8
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 98.0% of screened cell lines (common-essential)
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_006304

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10845
Approved symbol	SEM1
Name	SEM1 26S proteasome subunit
Location	7q21.3
Locus type	gene with protein product
Status	Approved
Aliases	DSS1, Shfdg1, ECD, SHSF1, FLJ42280, PSMD15
Ensembl gene	ENSG00000127922
Ensembl biotype	protein_coding
OMIM	601285
Entrez	7979

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 12 protein_coding, 8 protein_coding_CDS_not_defined, 6 nonsense_mediated_decay, 1 retained_intron

ENST00000248566, ENST00000356686, ENST00000413065, ENST00000417009, ENST00000444799, ENST00000449279, ENST00000466986, ENST00000476463, ENST00000482389, ENST00000488005, ENST00000493858, ENST00000606019, ENST00000611360, ENST00000613919, ENST00000615352, ENST00000616956, ENST00000617133, ENST00000618028, ENST00000618105, ENST00000619259, ENST00000622128, ENST00000622838, ENST00000623498, ENST00000623693, ENST00000927686, ENST00000927687, ENST00000927688

RefSeq mRNA: 9 — MANE Select: NM_006304 NM_001393898, NM_001393899, NM_001393900, NM_001393901, NM_001393902, NM_001393903, NM_001393905, NM_001393906, NM_006304

CCDS: CCDS5646, CCDS94146, CCDS94147, CCDS94148, CCDS94149, CCDS94150

Canonical transcript exons

ENST00000248566 — 3 exons

Exon	Start	End
ENSE00001039676	96709688	96709846
ENSE00001895287	96688762	96688966
ENSE00003750588	96694798	96694891

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 99.05.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 147.3440 / max 2282.4590, expressed in 1823 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
85001	80.3077	1817
85002	67.0026	1820
84999	0.0175	6
84998	0.0163	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	99.05	gold quality
tendon	UBERON:0000043	99.00	gold quality
tendon of biceps brachii	UBERON:0008188	98.99	gold quality
left testis	UBERON:0004533	98.98	gold quality
right testis	UBERON:0004534	98.95	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.82	gold quality
left adrenal gland	UBERON:0001234	98.56	gold quality
ganglionic eminence	UBERON:0004023	98.54	gold quality
left ovary	UBERON:0002119	98.51	gold quality
left adrenal gland cortex	UBERON:0035825	98.49	gold quality
ventricular zone	UBERON:0003053	98.47	gold quality
right adrenal gland	UBERON:0001233	98.40	gold quality
right adrenal gland cortex	UBERON:0035827	98.40	gold quality
testis	UBERON:0000473	98.32	gold quality
right ovary	UBERON:0002118	98.29	gold quality
islet of Langerhans	UBERON:0000006	98.22	gold quality
monocyte	CL:0000576	98.21	gold quality
adrenal cortex	UBERON:0001235	98.13	gold quality
adenohypophysis	UBERON:0002196	98.11	gold quality
gastrocnemius	UBERON:0001388	98.10	gold quality
right atrium auricular region	UBERON:0006631	98.10	gold quality
mucosa of transverse colon	UBERON:0004991	98.07	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.07	gold quality
stromal cell of endometrium	CL:0002255	98.06	gold quality
body of uterus	UBERON:0009853	98.04	gold quality
muscle of leg	UBERON:0001383	98.02	gold quality
popliteal artery	UBERON:0002250	98.02	gold quality
tibial artery	UBERON:0007610	98.02	gold quality
skin of abdomen	UBERON:0001416	98.01	gold quality
skin of leg	UBERON:0001511	97.99	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	64.87
E-GEOD-84465	yes	22.49
E-ANND-3	yes	15.31
E-MTAB-10042	yes	8.30
E-MTAB-9388	no	1701.56
E-MTAB-6819	no	934.00
E-GEOD-36552	no	139.83
E-GEOD-93593	no	8.28

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

6 targeting SEM1, 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-5010-3P	99.83	70.60	2357
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-18A-3P	99.56	65.68	1092
HSA-MIR-6792-5P	98.39	68.16	1330
HSA-MIR-3657	96.33	66.29	608

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 98.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 23)

• 3.1 angstrom crystal structure of approximately 90-kilodalton BRCA2 domain bound to DSS1, which reveals three oligonucleotide-binding (OB) folds and a helix-turn-helix (HTH) motif (PMID:12228710)
• DSS1, responsible for autism, was studied in a linkage disequilibrium model. (PMID:17406092)
• DSS1 has been shown to interact with components of the 26S proteasome in Saccharomyces cerevisiae and in human tumour cells (PMID:17563742)
• Data suggest that the R3IM motif of DSS1, in conjunction with the complexes of 19S RP and 20S core particle, regulates proteasome interaction through RPN3/S3 molecule, and utilizes a specific subset of poly-ubiquitinated p53 as a substrate. (PMID:18775730)
• The DSS1 c.143G>A variant is associated with reduced DSS1 expression at RNA and protein levels and altered traffic of the DSS1 protein from the cytoplasm to the nucleus. These alterations could impair DSS1 function and may be implicated in skin cancer. (PMID:20220765)
• p63 binds to an enhancer element in the SHFM1 locus and this element controls expression of DLX6 and DLX5 which are important for limb development. (PMID:20808887)
• DSS1 has a role in homologous recombinational repair in human cells (PMID:20817001)
• DSS1 protein is critically involved in the maintenance of the transformed phenotype in cervical cancer cells, and that it might be a specific, robust and reliable marker for early detection, diagnosis and trea (PMID:23024267)
• Mutation screening of the SHFM1 gene in familial breast/ovarian cancer cases. (PMID:23371468)
• Breast cancers with high DSS1 expression have worse prognosis and shorter relapse-free survival times. (PMID:24289229)
• SHFM1 confers cell cycle progression and resistance to p53 stabilizing drugs in gastric cancer cells. (PMID:25697906)
• by targeting RPA and mimicking DNA, DSS1 functions with BRCA2 in a two-component homologous recombination mediator complex in genome maintenance and tumor suppression (PMID:26145171)
• three phenotypic subregions within the SHFM1 locus link both size and genomic position of the chromosomal aberrations to the clinical variability seen in SHFM1 patients (PMID:26839112)
• DSS1 is a multifunctional and intrinsically disordered protein. (Review) (PMID:26944332)
• Promoter methylation plays a role in modulating DSS1 gene expression. Promoter hypomethylation is a frequent event in melanoma and squamous cell carcinoma and is closely linked to poor prognosis. (PMID:27825810)
• Our work introduces for the first time RAD52 as another interacting partner of DSS1 and shows that both proteins are important players in the SSA and BIR pathways of DSB repair. (PMID:31799622)
• DSS1 and ssDNA regulate oligomerization of BRCA2. (PMID:32609828)
• DSS1 allosterically regulates the conformation of the tower domain of BRCA2 that has dsDNA binding specificity for homologous recombination. (PMID:33011260)
• Cancer-causing BRCA2 missense mutations disrupt an intracellular protein assembly mechanism to disable genome maintenance. (PMID:33978741)
• Increased chemosensitivity via BRCA2-independent DNA damage in DSS1- and PCID2-depleted breast carcinomas. (PMID:34031538)
• The disordered PCI-binding human proteins CSNAP and DSS1 have diverged in structure and function. (PMID:34272906)
• SEM1 promotes tumor progression of glioblastoma via activating the akt signaling pathway. (PMID:37652287)
• DSS1 restrains BRCA2’s engagement with dsDNA for homologous recombination, replication fork protection, and R-loop homeostasis. (PMID:39152168)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	sem1	ENSDARG00000027899
mus_musculus	Sem1	ENSMUSG00000042541
rattus_norvegicus	Sem1	ENSRNOG00000010420

Protein

Protein identifiers

26S proteasome complex subunit SEM1 — P60896 (reviewed: P60896, Q6ZVN7)

Alternative names: 26S proteasome complex subunit DSS1, Deleted in split hand/split foot protein 1, Split hand/foot deleted protein 1, Split hand/foot malformation type 1 protein

All UniProt accessions (14): P60896, Q6ZVN7, A0A087WUG5, A0A087WXB9, A0A087WYU0, A0A087X1V0, A0A087X261, A0A096LP17, A0A096LP28, B7ZVW6, F2Z2L7, F2Z2N6, F2Z309, Q6IBB7

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. Component of the TREX-2 complex (transcription and export complex 2), composed of at least ENY2, GANP, PCID2, SEM1, and either centrin CETN2 or CETN3. The TREX-2 complex functions in docking export-competent ribonucleoprotein particles (mRNPs) to the nuclear entrance of the nuclear pore complex (nuclear basket). TREX-2 participates in mRNA export and accurate chromatin positioning in the nucleus by tethering genes to the nuclear periphery. Binds and stabilizes BRCA2 and is thus involved in the control of R-loop-associated DNA damage and thus transcription-associated genomic instability. R-loop accumulation increases in SEM1-depleted cells.

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 including SEM1, a base containing 6 ATPases and few additional components. Belongs to the TREX-2 complex (transcription and export complex 2), composed of at least ENY2, GANP, PCID2, SEM1, and either centrin CETN2 or CETN3. Component of the homologous recombination repair (HR) complex composed of ERCC5/XPG, BRCA2, PALB2, DSS1 and RAD51. Interacts with the C-terminal of BRCA2.

Subcellular location. Nucleus.

Tissue specificity. Expressed in limb bud, craniofacial primordia and skin.

Similarity. Belongs to the DSS1/SEM1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P60896-1	1	yes
Q6ZVN7-1	2

RefSeq proteins (9): NP_001380827, NP_001380828, NP_001380829, NP_001380830, NP_001380831, NP_001380832, NP_001380834, NP_001380835, NP_006295* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007834	DSS1_SEM1	Family
IPR041319	DUF5543	Family

Pfam: PF05160, PF17697

UniProt features (10 total): helix 3, chain 2, sequence variant 1, strand 1, region of interest 1, compositionally biased region 1, sequence conflict 1

Structure

Experimental structures (PDB)

129 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
3T5X	X-RAY DIFFRACTION	2.12
9K53	ELECTRON MICROSCOPY	2.5
8USB	ELECTRON MICROSCOPY	2.73
9MBP	ELECTRON MICROSCOPY	2.75
9DLP	ELECTRON MICROSCOPY	2.79
9NKG	ELECTRON MICROSCOPY	2.8
9E8I	ELECTRON MICROSCOPY	2.87
9E8H	ELECTRON MICROSCOPY	2.9
9NKF	ELECTRON MICROSCOPY	2.9
9BV3	ELECTRON MICROSCOPY	2.9
9K4J	ELECTRON MICROSCOPY	2.9
9T6L	ELECTRON MICROSCOPY	2.9
9U3L	ELECTRON MICROSCOPY	2.91
9NKI	ELECTRON MICROSCOPY	2.94
9DLV	ELECTRON MICROSCOPY	2.97
6MSB	ELECTRON MICROSCOPY	3
7W37	ELECTRON MICROSCOPY	3
8CVT	ELECTRON MICROSCOPY	3
9T6N	ELECTRON MICROSCOPY	3
9E8G	ELECTRON MICROSCOPY	3.01
9DLR	ELECTRON MICROSCOPY	3.08
9MBQ	ELECTRON MICROSCOPY	3.08
1MIU	X-RAY DIFFRACTION	3.1
7W38	ELECTRON MICROSCOPY	3.1
8USC	ELECTRON MICROSCOPY	3.1
9E8O	ELECTRON MICROSCOPY	3.1
9BV1	ELECTRON MICROSCOPY	3.1
9K4R	ELECTRON MICROSCOPY	3.1
9UPC	ELECTRON MICROSCOPY	3.14
9E8Q	ELECTRON MICROSCOPY	3.16

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P60896-F1	69.87	0.00
AF-Q6ZVN7-F1	51.68	0.00

Function

Pathways and Gene Ontology

Reactome pathways

182 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: 506 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, MORF_MTA1, REACTOME_DNA_REPLICATION, REACTOME_SIGNALING_BY_NOTCH, REACTOME_APC_C_CDH1_MEDIATED_DEGRADATION_OF_CDC20_AND_OTHER_APC_C_CDH1_TARGETED_PROTEINS_IN_LATE_MITOSIS_EARLY_G1, REACTOME_INNATE_IMMUNE_SYSTEM, MORF_MBD4, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GAANYNYGACNY_UNKNOWN, BASSO_B_LYMPHOCYTE_NETWORK, GOBP_RESPONSE_TO_PEPTIDE, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION

GO Biological Process (4): double-strand break repair via homologous recombination (GO:0000724), mRNA export from nucleus (GO:0006406), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), proteasome assembly (GO:0043248)

GO Molecular Function (2): ubiquitin binding (GO:0043130), protein binding (GO:0005515)

GO Cellular Component (7): proteasome complex (GO:0000502), nucleoplasm (GO:0005654), cytosol (GO:0005829), proteasome regulatory particle, lid subcomplex (GO:0008541), integrator complex (GO:0032039), protein-containing complex (GO:0032991), nucleus (GO:0005634)

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	2
recombinational repair	1
double-strand break repair	1
RNA export from nucleus	1
gene expression	1
mRNA transport	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
protein-containing complex assembly	1
ubiquitin-like protein binding	1
binding	1
intracellular protein-containing complex	1
endopeptidase complex	1
nuclear lumen	1
cytoplasm	1
proteasome regulatory particle	1
protein-containing complex	1
nuclear protein-containing complex	1
cellular_component	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

64 interactions, top by confidence:

A	B	Type	Score
BRCA2	SEM1	psi-mi:“MI:0915”(physical association)	0.830
BRCA2	SEM1	psi-mi:“MI:2364”(proximity)	0.830
SEM1	BRCA2	psi-mi:“MI:0915”(physical association)	0.830
PSMD11	PSMD12	psi-mi:“MI:0915”(physical association)	0.730
PSMD3	SEM1	psi-mi:“MI:0915”(physical association)	0.670
SEM1	PCID2	psi-mi:“MI:0915”(physical association)	0.670
ADRM1	PSMD11	psi-mi:“MI:0914”(association)	0.640
PCID2	SEM1	psi-mi:“MI:0407”(direct interaction)	0.610
PCID2	SEM1	psi-mi:“MI:0915”(physical association)	0.610
DR1	SEM1	psi-mi:“MI:0915”(physical association)	0.560
GRN	SEM1	psi-mi:“MI:0915”(physical association)	0.560
GTF2B	SEM1	psi-mi:“MI:0915”(physical association)	0.560
NF2	SEM1	psi-mi:“MI:0915”(physical association)	0.560
SEM1	GTF3C3	psi-mi:“MI:0915”(physical association)	0.560
SPTLC1	SEM1	psi-mi:“MI:0915”(physical association)	0.560
SEM1	JPH3	psi-mi:“MI:0915”(physical association)	0.560
SOD1	SEM1	psi-mi:“MI:0915”(physical association)	0.560
FUS	SEM1	psi-mi:“MI:0915”(physical association)	0.560
SEM1	LRRK2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (225): SHFM1 (Two-hybrid), PCID2 (Two-hybrid), SHFM1 (Synthetic Lethality), SHFM1 (Co-purification), RPA1 (Reconstituted Complex), SHFM1 (Co-crystal Structure), BRCA2 (Reconstituted Complex), SHFM1 (Reconstituted Complex), SHFM1 (Reconstituted Complex), SHFM1 (Affinity Capture-Western), SHFM1 (Two-hybrid), USP14 (Affinity Capture-Western), PSMD4 (Affinity Capture-Western), UBE3C (Affinity Capture-Western), PSMD14 (Affinity Capture-Western)

ESM2 similar proteins: A0JVA0, A0LTN7, A0QCZ8, A0QSB6, A0R5Z0, A1KIC1, A1R5G4, A1SL74, A4QGR5, A5U231, A6WCW8, A9WRD2, B2GJP2, B2HQI2, B8HGX6, C1AMX6, C1AVW7, C3PIP1, P0AAN8, P0C0V4, P0DUE9, P53423, P60896, P60897, P64740, P65092, P67648, P9WJ80, P9WJ81, P9WKQ6, P9WKQ7, P9WKX2, P9WKX3, P9WPC0, P9WPC1, Q0SGS7, Q3ZBR6, Q47QW3, Q4I9U7, Q4JX07

Diamond homologs: A8XLU5, O94742, P60896, P60897, P62499, Q3ZBR6, Q7SA04, Q95Y72, Q9VM46, O14140, Q54K21

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SEM1	“form complex”	“26S Proteasome”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 24 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	6	83.6×	2e-09
Proteasome assembly	8	81.6×	6e-12
Regulation of ornithine decarboxylase (ODC)	6	81.6×	2e-09
Vpu mediated degradation of CD4	6	79.7×	2e-09
Autodegradation of the E3 ubiquitin ligase COP1	6	79.7×	2e-09
Ubiquitin-dependent degradation of Cyclin D	6	79.7×	2e-09
Cross-presentation of soluble exogenous antigens (endosomes)	6	76.1×	2e-09
Vif-mediated degradation of APOBEC3G	6	76.1×	2e-09

GO biological processes:

GO term	Partners	Fold	FDR
proteasome-mediated ubiquitin-dependent protein catabolic process	7	15.9×	5e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	4
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1459945	NC_000007.13:g.(?95434042)(96747209_?)del	Pathogenic
1807695	GRCh37/hg19 7q21.3(chr7:95258682-96465856)x1	Pathogenic
974791	GRCh37/hg19 7q21.3(chr7:95931567-97254397)x1	Likely pathogenic

SpliceAI

2632 predictions. Top by Δscore:

Variant	Effect	Δscore
10:73134815:T:C	acceptor_gain	1.0000
10:73134815:T:TC	acceptor_gain	1.0000
10:73134820:CA:C	acceptor_gain	1.0000
10:73134821:A:AC	acceptor_gain	1.0000
10:73134821:A:C	acceptor_gain	1.0000
10:73136700:ATACC:A	donor_loss	1.0000
10:73136701:TA:T	donor_loss	1.0000
10:73136702:A:AC	donor_gain	1.0000
10:73136702:ACC:A	donor_loss	1.0000
10:73136703:C:CC	donor_gain	1.0000
10:73136703:CCA:C	donor_gain	1.0000
10:73136914:TGGCC:T	acceptor_gain	1.0000
10:73136915:GGCC:G	acceptor_gain	1.0000
10:73136916:GCC:G	acceptor_gain	1.0000
10:73136916:GCCC:G	acceptor_gain	1.0000
10:73136917:CC:C	acceptor_gain	1.0000
10:73136917:CCC:C	acceptor_gain	1.0000
10:73136917:CCCT:C	acceptor_gain	1.0000
10:73136918:CC:C	acceptor_gain	1.0000
10:73136919:C:CC	acceptor_gain	1.0000
10:73136922:C:CT	acceptor_gain	1.0000
10:73136924:C:CT	acceptor_gain	1.0000
10:73136925:A:T	acceptor_gain	1.0000
10:73136929:C:CT	acceptor_gain	1.0000
10:73136930:C:T	acceptor_gain	1.0000
10:73136931:C:CT	acceptor_gain	1.0000
10:73136931:C:T	acceptor_gain	1.0000
10:73136932:A:T	acceptor_gain	1.0000
10:73138069:CT:C	acceptor_gain	1.0000
10:73138071:C:CC	acceptor_gain	1.0000

AlphaMissense

470 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000010412 (7:96519913 A>G), RS1000024680 (7:96670491 G>A,C), RS1000037159 (7:96628410 A>G), RS1000049644 (7:96557080 T>G), RS1000051596 (7:96678002 C>G,T), RS1000063424 (7:96662349 A>G), RS1000088699 (7:96620152 T>C), RS1000092801 (7:96672202 A>G), RS1000131850 (7:96569116 G>A), RS1000142294 (7:96546267 C>A,T), RS1000159409 (7:96650176 A>G), RS1000193037 (7:96619374 T>C), RS1000193520 (7:96711321 GTTGAT>G), RS1000199100 (7:96575436 C>T), RS1000202394 (7:96570592 C>T)

Disease associations

OMIM: gene MIM:601285 | disease phenotypes:

GenCC curated gene-disease

Mondo (2): intellectual disability (MONDO:0001071), microcephaly (MONDO:0001149)

Orphanet (1): NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

8 total (9 of 8 shown, HPO-id order):

HPO	Term
HP:0000407	Sensorineural hearing impairment
HP:0000526	Aniridia
HP:0001171	Split hand
HP:0001839	Split foot
HP:0004050	Absent hand
HP:0004058	Hand monodactyly
HP:0006101	Finger syndactyly
HP:0012165	Oligodactyly
HP:0000252	Microcephaly

GWAS associations

35 associations (top):

Study	Trait	p-value
GCST000494_12	Bone mineral density (spine)	2.000000e-10
GCST000495_6	Bone mineral density (hip)	5.000000e-12
GCST000751_3	Attention deficit hyperactivity disorder	1.000000e-06
GCST000763_7	Immunoglobulin A	2.000000e-06
GCST002276_4	Bone mineral density	4.000000e-12
GCST002649_2	Nicotine glucouronidation	3.000000e-08
GCST003429_35	Morning vs. evening chronotype	1.000000e-08
GCST003654_13	Bone mineral density (Ward’s triangle area)	9.000000e-07
GCST003989_24	Chin dimples	5.000000e-56
GCST004350_4	Bone ultrasound measurement (velocity of sound)	2.000000e-07
GCST005795_24	Femoral neck bone mineral density	3.000000e-20
GCST005796_11	Lumbar spine bone mineral density	1.000000e-11
GCST006149_2	Frontotemporal dementia with GRN mutation (age at onset)	2.000000e-06
GCST006288_101	Heel bone mineral density	1.000000e-25
GCST006288_648	Heel bone mineral density	5.000000e-47
GCST006288_755	Heel bone mineral density	4.000000e-21
GCST006423_6	Fracture	2.000000e-19
GCST006479_128	Diverticular disease	3.000000e-10
GCST006630_12	Diastolic blood pressure	2.000000e-21
GCST006979_134	Heel bone mineral density	8.000000e-25
GCST006979_135	Heel bone mineral density	1.000000e-74
GCST006979_136	Heel bone mineral density	4.000000e-14
GCST007565_128	Morning person	1.000000e-13
GCST007565_156	Morning person	4.000000e-29
GCST007576_9	Chronotype	4.000000e-29
GCST010702_148	Subcortical volume (MOSTest)	8.000000e-13
GCST010703_308	Brain morphology (MOSTest)	1.000000e-25
GCST011616_16	Cortical volume	7.000000e-13
GCST012490_163	Femur bone mineral density x serum urate levels interaction	4.000000e-11
GCST90002385_142	High light scatter reticulocyte count	3.000000e-11

EFO canonical traits (14, from GWAS)

EFO ID	Trait name
EFO:0004747	protein measurement
EFO:0006507	nicotine glucuronidation measurement
EFO:0007785	femoral neck bone mineral density
EFO:0004514	bone quantitative ultrasound measurement
EFO:0007701	spine bone mineral density
EFO:0004847	age at onset
EFO:0009270	heel bone mineral density
EFO:0009959	diverticular disease
EFO:0006336	diastolic blood pressure
EFO:0008328	chronotype measurement
EFO:0004346	neuroimaging measurement
EFO:0004531	urate measurement
EFO:0007986	reticulocyte count
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2364701 (PROTEIN COMPLEX)

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

62 potent at pChembl≥5 of 63 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
8.29	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
5.70	IC50	2000	nM	BORTEZOMIB
5.66	IC50	2170	nM	CHEMBL3237873

PubChem BioAssay actives

60 with measured affinity, of 133 total; 32 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
(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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, increases expression	3
bisphenol A	affects expression, decreases expression	2
sodium arsenite	increases expression	2
Cyclosporine	increases expression	2
bisphenol F	affects cotreatment, affects expression	1
dicrotophos	decreases expression	1
beta-lapachone	increases expression	1
isobutyl alcohol	affects cotreatment, decreases expression, increases abundance	1
bicalutamide	increases expression	1
CD 437	decreases expression	1
chloropicrin	increases expression	1
K 7174	decreases expression	1
3-(4’-hydroxy-3’-adamantylbiphenyl-4-yl)acrylic acid	decreases expression	1
picoxystrobin	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	affects cotreatment, increases expression	1
Fulvestrant	decreases methylation	1
Antimycin A	increases expression	1
Copper	affects binding, decreases expression	1
Dexamethasone	affects cotreatment, affects expression	1
Disulfiram	affects binding, decreases expression	1
Gasoline	affects cotreatment, decreases expression, increases abundance	1
Indomethacin	affects cotreatment, affects expression	1
Phenobarbital	affects expression	1
Plant Extracts	affects cotreatment, increases expression	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, decreases expression, increases abundance	1
Rotenone	decreases expression	1
Selenium	decreases expression	1
Tetradecanoylphorbol Acetate	affects cotreatment, increases expression	1

ChEMBL screening assays

26 unique, capped per target: 26 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)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
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