USP9X

Summary

USP9X (ubiquitin specific peptidase 9 X-linked, HGNC:12632) is a protein-coding gene on chromosome Xp11.4, encoding Ubiquitin carboxyl-terminal hydrolase 9X (Q93008). Deubiquitinase involved both in the processing of ubiquitin precursors and of ubiquitinated proteins. It is a selective cancer dependency (DepMap: 68.8% of cell lines) and haploinsufficient (ClinGen: sufficient evidence).

This gene is a member of the peptidase C19 family and encodes a protein that is similar to ubiquitin-specific proteases. Though this gene is located on the X chromosome, it escapes X-inactivation. Mutations in this gene have been associated with Turner syndrome. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.

Source: NCBI Gene 8239 — RefSeq curated summary.

At a glance

• Gene–disease (curated): X-linked syndromic intellectual disability (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 1,605 total — 75 pathogenic, 54 likely-pathogenic
• Phenotypes (HPO): 117
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 6 cancer types
• Cancer dependency (DepMap): dependent in 68.8% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001039591

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12632
Approved symbol	USP9X
Name	ubiquitin specific peptidase 9 X-linked
Location	Xp11.4
Locus type	gene with protein product
Status	Approved
Aliases	DFFRX, FAF, FAF-X, MRX99
Ensembl gene	ENSG00000124486
Ensembl biotype	protein_coding
OMIM	300072
Entrez	8239

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 10 protein_coding, 5 retained_intron, 4 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000324545, ENST00000378308, ENST00000462850, ENST00000463829, ENST00000465386, ENST00000467173, ENST00000485180, ENST00000487625, ENST00000703986, ENST00000703987, ENST00000704649, ENST00000704650, ENST00000704651, ENST00000704652, ENST00000704653, ENST00000704654, ENST00000704655, ENST00000704656, ENST00000929529, ENST00000971820

RefSeq mRNA: 4 — MANE Select: NM_001039591 NM_001039590, NM_001039591, NM_001410748, NM_001410749

CCDS: CCDS43930, CCDS55403, CCDS94593, CCDS94594

Canonical transcript exons

ENST00000378308 — 45 exons

Exon	Start	End
ENSE00000847597	41129000	41129145
ENSE00000847598	41131457	41131536
ENSE00001285795	41169995	41170235
ENSE00001476935	41136804	41137022
ENSE00001477020	41232387	41236579
ENSE00001477164	41123471	41123724
ENSE00001607399	41162790	41162877
ENSE00001639109	41205303	41205493
ENSE00001642664	41148369	41148575
ENSE00001643852	41134725	41134837
ENSE00001652621	41150921	41151057
ENSE00001674784	41140966	41141217
ENSE00001678534	41144522	41144626
ENSE00001691023	41152948	41153081
ENSE00001712847	41171838	41171958
ENSE00001720294	41167482	41167577
ENSE00001727487	41168007	41168218
ENSE00001752064	41140656	41140771
ENSE00001763349	41165872	41166214
ENSE00001775538	41143291	41143443
ENSE00001779150	41170470	41170619
ENSE00001782464	41141293	41141431
ENSE00003472082	41198528	41198750
ENSE00003476127	41224742	41224962
ENSE00003479238	41218372	41218597
ENSE00003496642	41196251	41196359
ENSE00003499577	41201060	41201280
ENSE00003500153	41229253	41229409
ENSE00003501573	41187992	41188117
ENSE00003515665	41214568	41214709
ENSE00003523603	41225049	41225137
ENSE00003544249	41215899	41216652
ENSE00003551825	41184397	41184675
ENSE00003568838	41230501	41230596
ENSE00003575843	41217220	41217343
ENSE00003586919	41229567	41229779
ENSE00003599116	41186517	41186642
ENSE00003608312	41210509	41210682
ENSE00003618555	41219102	41219231
ENSE00003673625	41183998	41184128
ENSE00003680861	41223217	41223402
ENSE00003685722	41197364	41197510
ENSE00003692132	41196592	41196738
ENSE00003694611	41189309	41189475
ENSE00003843567	41085445	41086109

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 98.74.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 35.1159 / max 1302.5797, expressed in 1819 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
196008	22.2670	1810
196006	3.4600	1446
196013	3.2876	1463
196009	1.9221	1169
196011	1.7342	1186
196010	0.8609	592
196012	0.6814	388
196022	0.3682	181
196007	0.2595	103
196020	0.2152	69

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
middle frontal gyrus	UBERON:0002702	98.74	gold quality
endometrium epithelium	UBERON:0004811	98.74	gold quality
secondary oocyte	CL:0000655	98.62	gold quality
paraflocculus	UBERON:0005351	98.27	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.23	gold quality
jejunum	UBERON:0002115	97.86	gold quality
substantia nigra pars reticulata	UBERON:0001966	97.82	gold quality
jejunal mucosa	UBERON:0000399	97.79	gold quality
trabecular bone tissue	UBERON:0002483	97.75	gold quality
oviduct epithelium	UBERON:0004804	97.72	gold quality
frontal pole	UBERON:0002795	97.71	gold quality
lateral globus pallidus	UBERON:0002476	97.70	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.70	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	97.67	gold quality
substantia nigra pars compacta	UBERON:0001965	97.51	gold quality
oocyte	CL:0000023	97.46	gold quality
biceps brachii	UBERON:0001507	97.44	gold quality
cervix squamous epithelium	UBERON:0006922	97.41	gold quality
mammary duct	UBERON:0001765	97.40	gold quality
entorhinal cortex	UBERON:0002728	97.35	gold quality
dorsal root ganglion	UBERON:0000044	97.34	gold quality
seminal vesicle	UBERON:0000998	97.33	gold quality
cardia of stomach	UBERON:0001162	97.29	gold quality
renal medulla	UBERON:0000362	97.28	gold quality
epithelium of mammary gland	UBERON:0003244	97.26	gold quality
Brodmann (1909) area 10	UBERON:0013541	97.18	gold quality
mucosa of sigmoid colon	UBERON:0004993	97.16	gold quality
body of tongue	UBERON:0011876	97.16	gold quality
inferior olivary complex	UBERON:0002127	97.15	gold quality
adrenal tissue	UBERON:0018303	97.14	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ENAD-17	no	410.15
E-MTAB-6524	no	353.55
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 68.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• FAM associates with E-cadherin and beta-catenin during trafficking to the plasma membrane (PMID:14742711)
• identified the ubiquitin-protease FAM/USP9X as a binding partner of Itch. The association between Itch and FAM/USP9X was confirmed in vitro by glutathione S-transferase pulldown and in vivo through coimmunoprecipation (PMID:17038327)
• NUAK1 and MARK4 are substrates of USP9X (PMID:18254724)
• MARCH7 can be stabilized by both USP9X and USP7, which deubiquitylate MARCH7 in the cytosol and nucleus, respectively (PMID:18410486)
• Smad4 is monoubiquitinated in lysine 519 in vivo, a modification that inhibits Smad4 by impeding association with phospho-Smad2; FAM reverts this negative modification, re-empowering Smad4 function. (PMID:19135894)
• the deubiquitinase USP9X stabilizes MCL1 and thereby promotes cell survival; deubiquitinases may stabilize labile oncoproteins in human malignancies (PMID:20023629)
• Zymophagy, a novel selective autophagy pathway mediated by VMP1-USP9x-p62, prevents pancreatic cell death. (PMID:21173155)
• Ubiquitin-cycle inhibition represents a novel and effective approach to blocking Bcr-Abl kinase signaling and reducing Mcl-1 levels to engage chronic myelogenous leukemia cell apoptosis. (PMID:21248063)
• alpha-Synuclein fate is determined by USP9X-regulated monoubiquitination (PMID:22065755)
• Our results suggest that ubiquitin-specific protease 9X (USP9X) is by far the most active deubiquitinase acting on Ub-PEX5, both in female rat liver and HeLa cells. (PMID:22371489)
• the deubiquitinase USP9X as a novel mTORC1 and -2 binding partner that negatively regulates mTOR activity and skeletal muscle differentiation. (PMID:22544753)
• loss of Usp9x enhances transformation and protects pancreatic cancer cells from anoikis (PMID:22699621)
• The resulting USP9X-deficient cancer cells exhibited increased activation of apoptotic pathways. (PMID:22895071)
• Usp9x plays an important role in stabilizing SMN and the SMN complex, likely via antagonizing Ub-dependent SMN degradation. (PMID:23112048)
• Mcl-1, Bcl-xL and USP9X overexpression are tumor survival mechanisms protective against chemotherapy. (PMID:23171055)
• USP9X is an important regulatory protein of SMURF1. (PMID:23184937)
• a large set of SOX2-associated proteins in DAOY medulloblastoma cells (PMID:23667531)
• USP9X mutations may have a role in X-linked intellectual disability and disrupt neuronal cell migration and growth (PMID:24607389)
• Although USP9X may function as a tumor-suppressor during the establishment of PDAC, data presented here argue that USP9X promotes cell growth in advanced PDAC cells when PDAC is typically diagnosed. (PMID:24841553)
• Our analysis of clinical HCC samples verifies that miR-26b also targets USP9X expression to inhibit the EMT of hepatocytes (PMID:24890815)
• Noxa upregulation reduces the availability of Usp9x to Mcl-1, thereby promoting its ubiquitination and degradation, leading to the apoptosis of neoplastic cells. (PMID:24991768)
• USP9X downregulation renders breast cancer cells resistant to tamoxifen. (PMID:25028367)
• These data support the use of MCL1 expression as a predictive biomarker for USP9X inhibitors in non-small cell lung cancer therapy (PMID:25692226)
• The mammalian PRICKLE-interactome was defined, identifying prickle-interacting proteins that localize to synapses and a novel interacting partner, USP9X, a substrate-specific de-ubiquitinase. PRICKLE and USP9X interact through their carboxy-termini; and USP9X de-ubiquitinates PRICKLE, protecting it from proteasomal degradation. (PMID:25763846)
• the novel compound EOAI3402143 dose-dependently inhibited Usp9x and Usp24 activity, increased tumor cell apoptosis, and fully blocked or regressed myeloma tumors in mice. (PMID:25814533)
• biological relevance of the ICP0- USP9X complex in HSV-1 infection (PMID:26596467)
• study reports for the first time that USP9X is a deubiquitinase of Angiomotin-like 2 (AMOTL2) and that AMOTL2 mono-ubiquitination is required for YAP inhibition (PMID:26598551)
• USP9x interacted with and stabilized beta-catenin through deubiquitination to mediate transcription of the decoy receptors in breast cancer cells (PMID:26717875)
• identify USP9X as a novel regulator of EGFR endocytosis (PMID:26748853)
• We examined the role of USP9X in the primary cilium of affected females with ciliopathy syndromes and found that endogenous USP9X localizes along the length of the ciliary axoneme, so its loss of function could disrupt cilium-regulated processes. (PMID:26833328)
• found that USP9X regulated the expression and stability of CLASPIN in an S-phase-specific manner. USP9X depletion profoundly impairs the progression of DNA replication forks, causing unscheduled termination events with a frequency similar to CLASPIN depletion, resulting in excessive endogenous DNA damage (PMID:26921344)
• BAG3 was found to positively regulate Mcl-1 levels by binding to and inhibiting USP9X. Our data show that BAG3 and Mcl-1 are key mediators of resistance to chemotherapy in ovarian cancer (PMID:27120977)
• The authors find that primary human aggressive B-cell lymphoma samples exhibit high USP9X expression that correlate with XIAP overexpression. (PMID:27317434)
• USP9X possibly promotes head and neck cancer cell proliferation through the mTOR pathway. (PMID:27374971)
• these findings demonstrate that USP9X is a novel regulator of Von Hippel-Lindau protein stability, and USP9X may be a therapeutic target for treatment of Von Hippel-Lindau protein-related tumors (PMID:27517496)
• High USP9X expression is associated with basal-like breast cancer. (PMID:27593927)
• knockdown of USP9X was shown to confer resistance to apoptosis following pediatric T-cell acute lymphoblastic leukemia relevant chemotherapy drug treatment in Jurkat leukemia cells (PMID:27602765)
• study identified USP9X frameshift mutations that could possibly contribute to some microsatellite instability-high colorectal cancers (PMID:27770309)
• USP9X stabilizes beta-catenin and activates Wnt/beta-catenin signal pathway to promote glioma cell proliferation and survival. (PMID:27783990)
• USP9x-SMAD4 Interaction is associated with Breast Cancer Metastasis. (PMID:28115363)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	usp9	ENSDARG00000013708
mus_musculus	Usp9x	ENSMUSG00000031010
rattus_norvegicus	Usp9x	ENSRNOG00000003261

Paralogs (71): USP2 (ENSG00000036672), USP28 (ENSG00000048028), USP36 (ENSG00000055483), USP13 (ENSG00000058056), USP33 (ENSG00000077254), USP40 (ENSG00000085982), USP48 (ENSG00000090686), USP14 (ENSG00000101557), USP11 (ENSG00000102226), USP10 (ENSG00000103194), USP31 (ENSG00000103404), USP42 (ENSG00000106346), USP5 (ENSG00000111667), USP4 (ENSG00000114316), USP9Y (ENSG00000114374), USP34 (ENSG00000115464), USP35 (ENSG00000118369), USP45 (ENSG00000123552), USP22 (ENSG00000124422), USP6 (ENSG00000129204), USP29 (ENSG00000131864), USP26 (ENSG00000134588), USP30 (ENSG00000135093), USP15 (ENSG00000135655), USP37 (ENSG00000135913), USP44 (ENSG00000136014), USP20 (ENSG00000136878), USP8 (ENSG00000138592), USP3 (ENSG00000140455), USP21 (ENSG00000143258), USP43 (ENSG00000154914), USP25 (ENSG00000155313), USP16 (ENSG00000156256), USP24 (ENSG00000162402), USP1 (ENSG00000162607), USP49 (ENSG00000164663), USP38 (ENSG00000170185), USP50 (ENSG00000170236), USP47 (ENSG00000170242), USP32 (ENSG00000170832)

Protein

Protein identifiers

Ubiquitin carboxyl-terminal hydrolase 9X — Q93008 (reviewed: Q93008)

Alternative names: Deubiquitinating enzyme FAF-X, Fat facets in mammals, Fat facets protein-related, X-linked, Ubiquitin thioesterase FAF-X, Ubiquitin-specific protease 9, X chromosome, Ubiquitin-specific-processing protease FAF-X

All UniProt accessions (10): A0A994J4K9, A0A994J4R6, A0A994J4T3, A0A994J4T8, A0A994J583, A0A994J588, A0A994J6S4, A0A994J766, A0A994J7K1, Q93008

UniProt curated annotations — full annotation on UniProt →

Function. Deubiquitinase involved both in the processing of ubiquitin precursors and of ubiquitinated proteins. May therefore play an important regulatory role at the level of protein turnover by preventing degradation of proteins through the removal of conjugated ubiquitin. Specifically hydrolyzes ‘Lys-11’-, followed by ‘Lys-63’-, ‘Lys-48’- and ‘Lys-6’-linked polyubiquitins chains. Essential component of TGF-beta/BMP signaling cascade. Specifically deubiquitinates monoubiquitinated SMAD4, opposing the activity of E3 ubiquitin-protein ligase TRIM33. Deubiquitinates alkylation repair enzyme ALKBH3. OTUD4 recruits USP7 and USP9X to stabilize ALKBH3, thereby promoting the repair of alkylated DNA lesions. Deubiquitinates RNA demethylase enzyme ALKBH5, promoting its stability. Deubiquitinates mTORC2 complex component RICTOR at ‘Lys-294’ by removing ‘Lys-63’-linked polyubiquitin chains, stabilizing RICTOR and enhancing its binding to MTOR, thus promoting mTORC2 complex assembly. Regulates chromosome alignment and segregation in mitosis by regulating the localization of BIRC5/survivin to mitotic centromeres. Involved in axonal growth and neuronal cell migration. Regulates cellular clock function by enhancing the protein stability and transcriptional activity of the core circadian protein BMAL1 via its deubiquitinating activity. Acts as a regulator of peroxisome import by mediating deubiquitination of PEX5: specifically deubiquitinates PEX5 monoubiquitinated at ‘Cys-11’ following its retrotranslocation into the cytosol, resetting PEX5 for a subsequent import cycle. Deubiquitinates PEG10. Inhibits the activation of the Hippo signaling pathway via deubiquitination of AMOTL2 at ‘Lys-347’ and ‘Lys-408’ which prohibits its interaction with and activation of LATS2. Loss of LATS2 activation and subsequent loss of YAP1 phosphorylation results in an increase in YAP1-driven transcription of target genes.

Subunit / interactions. Interacts with SMAD4, MARK4, NUAK1 and BIRC5/survivin. Interacts with DCX. Interacts with OTUD4 and USP7; the interaction is direct.

Subcellular location. Cytoplasm. Cytosol. Cell projection. Growth cone. Cytoskeleton. Cilium axoneme.

Tissue specificity. Widely expressed in embryonic and adult tissues.

Disease relevance. Intellectual developmental disorder, X-linked 99 (XLID99) [MIM:300919] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked forms, while syndromic forms present with associated physical, neurological and/or psychiatric manifestations. The disease may be caused by variants affecting the gene represented in this entry. Intellectual developmental disorder, X-linked 99, syndromic, female-restricted (MRXS99F) [MIM:300968] A form of intellectual disability, a disorder characterized by significantly below average general intellectual functioning, associated with impairments in adaptive behavior and manifested during the developmental period. MRXS99F affected females manifest intellectual disability, developmental delay, facial dysmorphism, short stature, and distinct congenital malformations comprising choanal atresia, anal abnormalities, post-axial polydactyly, heart defects, hypomastia, cleft palate/bifid uvula, progressive scoliosis, and structural brain abnormalities. Inheritance is X-linked dominant. The disease is caused by variants affecting the gene represented in this entry.

Induction. By growth factors.

Miscellaneous. Escapes X-inactivation.

Similarity. Belongs to the peptidase C19 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q93008-1	1, Short	yes
Q93008-3	2, Long

RefSeq proteins (4): NP_001034679, NP_001034680, NP_001397677, NP_001397678 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001394	Peptidase_C19_UCH	Domain
IPR016024	ARM-type_fold	Homologous_superfamily
IPR018200	USP_CS	Conserved_site
IPR021905	DUF3517	Domain
IPR028889	USP	Domain
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR050164	Peptidase_C19	Family
IPR055176	UBP24/USP9X/USP9Y_UBL	Domain
IPR056850	ARM_UBP34_24_USP9X_Y	Domain

Pfam: PF00443, PF12030, PF22900, PF25010

UniProt features (199 total): helix 94, strand 40, turn 18, sequence conflict 9, sequence variant 8, modified residue 7, compositionally biased region 6, binding site 4, region of interest 4, mutagenesis site 4, active site 2, chain 1, domain 1, splice variant 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
5VBD	X-RAY DIFFRACTION	1.5
5WCH	X-RAY DIFFRACTION	2.5
7YXY	ELECTRON MICROSCOPY	3.1
7YXX	ELECTRON MICROSCOPY	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q93008-F1	80.06	0.33

Functional residue map

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

Catalytic / active sites (2): 1566 (nucleophile); 1879 (proton acceptor)

Ligand- & substrate-binding residues (4): 1727; 1729; 1771; 1774

Post-translational modifications (7): 588, 590, 1600, 2443, 2540, 2547, 2551

Mutagenesis-validated functional residues (4):

Position	Phenotype
1566	does not restore rictor expression levels when introduced into cells where endogenous usp9x has been silenced.
1566	abolished deubiquitinase activity.
1727	strongly decreased deubiquitinase activity.
1729	strongly decreased deubiquitinase activity.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-2173795	Downregulation of SMAD2/3:SMAD4 transcriptional activity
R-HSA-5689880	Ub-specific processing proteases
R-HSA-8866652	Synthesis of active ubiquitin: roles of E1 and E2 enzymes
R-HSA-9013420	RHOU GTPase cycle
R-HSA-9013424	RHOV GTPase cycle
R-HSA-9033241	Peroxisomal protein import
R-HSA-977225	Amyloid fiber formation

MSigDB gene sets: 620 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GOBP_CIRCADIAN_RHYTHM, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOBP_POSITIVE_REGULATION_OF_PROTEIN_BINDING, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_REGULATION_OF_PROTEIN_BINDING, REACTOME_SIGNALING_BY_TGF_BETA_RECEPTOR_COMPLEX, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_TOR_SIGNALING, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_GROWTH, GOBP_MACROMOLECULE_CATABOLIC_PROCESS

GO Biological Process (30): negative regulation of transcription by RNA polymerase II (GO:0000122), neuron migration (GO:0001764), DNA alkylation repair (GO:0006307), chromosome segregation (GO:0007059), transforming growth factor beta receptor signaling pathway (GO:0007179), female gamete generation (GO:0007292), intracellular protein localization (GO:0008104), cell migration (GO:0016477), protein import into peroxisome matrix, receptor recycling (GO:0016562), protein ubiquitination (GO:0016567), protein deubiquitination (GO:0016579), BMP signaling pathway (GO:0030509), regulation of protein stability (GO:0031647), positive regulation of protein binding (GO:0032092), negative regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032435), monoubiquitinated protein deubiquitination (GO:0035520), regulation of circadian rhythm (GO:0042752), rhythmic process (GO:0048511), axon extension (GO:0048675), protein stabilization (GO:0050821), cell division (GO:0051301), cilium assembly (GO:0060271), cytosolic ciliogenesis (GO:0061824), protein K63-linked deubiquitination (GO:0070536), protein deubiquitination involved in ubiquitin-dependent protein catabolic process (GO:0071947), positive regulation of TORC2 signaling (GO:1904515), amyloid fibril formation (GO:1990000), proteolysis (GO:0006508), protein import into peroxisome matrix (GO:0016558), negative regulation of cilium assembly (GO:1902018)

GO Molecular Function (12): cysteine-type endopeptidase activity (GO:0004197), cysteine-type deubiquitinase activity (GO:0004843), cysteine-type peptidase activity (GO:0008234), K63-linked deubiquitinase activity (GO:0061578), co-SMAD binding (GO:0070410), deubiquitinase activity (GO:0101005), molecular sequestering activity (GO:0140313), K11-linked deubiquitinase activity (GO:0180017), K48-linked deubiquitinase activity (GO:1990380), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (10): nucleus (GO:0005634), cytoplasm (GO:0005737), centrosome (GO:0005813), cytosol (GO:0005829), cilium (GO:0005929), axoneme (GO:0005930), membrane (GO:0016020), growth cone (GO:0030426), cytoskeleton (GO:0005856), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
RHO GTPase cycle	2
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	1
Deubiquitination	1
Protein ubiquitination	1
Protein localization	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
deubiquitinase activity	4
transforming growth factor beta receptor superfamily signaling pathway	2
cysteine-type peptidase activity	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
cell migration	1
generation of neurons	1
DNA repair	1
cell cycle process	1
cellular response to transforming growth factor beta stimulus	1
gamete generation	1
macromolecule localization	1
cell motility	1
receptor recycling	1
protein import into peroxisome matrix	1
protein modification by small protein conjugation	1
cysteine-type deubiquitinase activity	1
protein modification by small protein removal	1
cellular response to BMP stimulus	1
regulation of biological quality	1
protein binding	1
regulation of protein binding	1
positive regulation of binding	1
regulation of proteasomal ubiquitin-dependent protein catabolic process	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
negative regulation of proteasomal protein catabolic process	1
negative regulation of ubiquitin-dependent protein catabolic process	1
protein deubiquitination	1
circadian rhythm	1
regulation of biological process	1
biological_process	1
axonogenesis	1
neuron projection extension	1
regulation of protein stability	1
endopeptidase activity	1
peptidase activity	1
SMAD binding	1
ubiquitin-like protein peptidase activity	1

Protein interactions and networks

STRING

2566 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
USP9X	WWP1	Q9H0M0	804
USP9X	FOXO3	O43524	796
USP9X	MARK4	Q96L34	770
USP9X	MCL1	Q07820	758
USP9X	ZFX	P17010	747
USP9X	ZUP1	Q96AP4	745
USP9X	KDM5C	P41229	732
USP9X	USP5	P45974	719
USP9X	HUWE1	Q7Z6Z7	703
USP9X	NUAK1	O60285	694
USP9X	UTY	O14607	693
USP9X	UCHL5	Q9Y5K5	674
USP9X	USP13	Q92995	670
USP9X	KDM5D	Q9BY66	670
USP9X	SMURF1	Q9HCE7	668

IntAct

225 interactions, top by confidence:

A	B	Type	Score
MCL1	BAK1	psi-mi:“MI:0914”(association)	0.960
VHL	ELOC	psi-mi:“MI:0914”(association)	0.920
MCL1	HUWE1	psi-mi:“MI:0914”(association)	0.880
HUWE1	MCL1	psi-mi:“MI:0914”(association)	0.880
AXIN1	APC	psi-mi:“MI:0914”(association)	0.850
HEXIM2	AHCYL1	psi-mi:“MI:0914”(association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
MCL1	USP9X	psi-mi:“MI:0407”(direct interaction)	0.680
USP9X	MCL1	psi-mi:“MI:0914”(association)	0.680
USP9X	MCL1	psi-mi:“MI:0915”(physical association)	0.680
MCL1	USP9X	psi-mi:“MI:0915”(physical association)	0.680
USP9X	MCL1	psi-mi:“MI:0204”(deubiquitination reaction)	0.680
PKN3	ARHGAP10	psi-mi:“MI:0914”(association)	0.680
PEG10	RTL8C	psi-mi:“MI:0914”(association)	0.670
VHL	USP9X	psi-mi:“MI:0915”(physical association)	0.640
VHL	USP9X	psi-mi:“MI:0403”(colocalization)	0.640
RPS6KA3	ROCK2	psi-mi:“MI:0914”(association)	0.640
CAMKV	AP3B1	psi-mi:“MI:0914”(association)	0.640
PIK3R2	IRS4	psi-mi:“MI:0914”(association)	0.640
ATXN7L3	USP27X	psi-mi:“MI:0914”(association)	0.640
DHX38	DHX16	psi-mi:“MI:0914”(association)	0.630
OPG200	IKBKB	psi-mi:“MI:0914”(association)	0.620

BioGRID (693): USP9X (Affinity Capture-MS), MLLT4 (Reconstituted Complex), USP9X (Affinity Capture-Western), USP9X (Affinity Capture-MS), USP9X (Affinity Capture-MS), USP9X (Affinity Capture-MS), USP9X (Affinity Capture-RNA), USP9X (Affinity Capture-MS), PRPF8 (Co-fractionation), USP9X (Affinity Capture-Western), USP9X (Affinity Capture-Western), USP9X (Affinity Capture-MS), USP9X (Affinity Capture-MS), USP9X (Affinity Capture-MS), USP9X (Affinity Capture-MS)

ESM2 similar proteins: A0A8J1LLF7, A0A974H8H3, A0MQH0, A4FUD6, A5HK05, B3DLA6, P11029, P11497, P42694, P54198, Q13085, Q25BN1, Q28559, Q4R4U1, Q504Q3, Q5R5F8, Q5R660, Q5R8I6, Q5RCC1, Q5SWU9, Q5ZIT8, Q6DFV5, Q6IE70, Q6NYU2, Q6P1X5, Q6TUI4, Q6TV19, Q80YV4, Q8BGF7, Q8BHL5, Q8BPU7, Q8C176, Q8CIQ7, Q8IZD9, Q8K0F1, Q8R418, Q8R5L3, Q8VHE0, Q923S8, Q92556

Diamond homologs: A0A0R4IB93, A0JM59, A5PMR2, A5PN09, A6NNY8, A6QNM7, A7Z056, B1AY13, B1WBD7, D2HBJ8, D6RBM5, E1C213, E7F6T8, E9Q9U0, F6Z5C0, F8VPU6, F8VPZ3, M9PD06, O00507, O22207, O60079, O74442, O94269, O94966, O96612, P0C7I0, P0C8Z3, P0CAQ1, P35125, P39538, P40453, P51784, P53874, P55824, P70398, Q01988, Q09738, Q0V9G5, Q28CN3, Q2HJE4

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
USP9X	up-regulates	SMAD4	deubiquitination
USP9X	“down-regulates activity”	EPS15	deubiquitination
USP9X	“up-regulates quantity by stabilization”	SMN1	deubiquitination
USP9X	“up-regulates quantity”	UBA52	cleavage
USP9X	“up-regulates quantity”	RPS27A	cleavage
USP9X	“up-regulates quantity”	Ubiquitin	cleavage
CDK1	“up-regulates activity”	USP9X	phosphorylation
CyclinB/CDK1	“up-regulates activity”	USP9X	phosphorylation
CDC14B	“down-regulates quantity by destabilization”	USP9X	dephosphorylation
USP9X	“up-regulates quantity by stabilization”	WT1	deubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 233 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
MAP kinase activation	6	11.8×	2e-03
NOD1/2 Signaling Pathway	5	10.1×	7e-03
Interleukin-17 signaling	6	9.7×	3e-03
Toll Like Receptor 10 (TLR10) Cascade	7	9.6×	2e-03
Toll Like Receptor 5 (TLR5) Cascade	7	9.6×	2e-03
MyD88 cascade initiated on plasma membrane	7	9.1×	2e-03
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	7	8.5×	2e-03
MyD88 dependent cascade initiated on endosome	7	8.5×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein autophosphorylation	12	8.3×	2e-05
protein phosphorylation	22	7.1×	1e-09
cell surface receptor protein tyrosine kinase signaling pathway	8	6.6×	8e-03
positive regulation of MAPK cascade	13	5.0×	1e-03
intracellular signal transduction	17	3.1×	1e-02

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 6 cancer types — CHOL, HCC, LMS, NPC, PRAD, WDTC.

Clinical variants and AI predictions

ClinVar

1605 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	75
Likely pathogenic	54
Uncertain significance	574
Likely benign	270
Benign	146

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1034402	NM_001039591.3(USP9X):c.2026C>T (p.Gln676Ter)	Pathogenic
1068468	NM_001039591.3(USP9X):c.6659dup (p.Tyr2220Ter)	Pathogenic
1074387	NM_001039591.3(USP9X):c.144dup (p.Asp49fs)	Pathogenic
1098318	NM_001039591.3(USP9X):c.3066G>A (p.Trp1022Ter)	Pathogenic
1184099	NM_001039591.3(USP9X):c.3060_3064del (p.Phe1020fs)	Pathogenic
1193570	NM_001039591.3(USP9X):c.5053G>A (p.Asp1685Asn)	Pathogenic
1217077	NM_001039591.3(USP9X):c.4037dup (p.His1347fs)	Pathogenic
1254438	NM_001039591.3(USP9X):c.82dup (p.Leu28fs)	Pathogenic
127090	NM_001039591.3(USP9X):c.6278T>A (p.Leu2093His)	Pathogenic
127091	NM_001039591.3(USP9X):c.7526del (p.Gln2509fs)	Pathogenic
1299503	NM_001039591.3(USP9X):c.52C>T (p.Gln18Ter)	Pathogenic
1301402	NM_001039591.3(USP9X):c.1840_1843del (p.Thr614fs)	Pathogenic
1338821	NM_001039591.3(USP9X):c.1812_1815del (p.Gln605fs)	Pathogenic
1695974	NM_001039591.3(USP9X):c.6679_6685delinsTCCTG (p.Lys2227_Tyr2229delinsSerTer)	Pathogenic
1698973	NM_001039591.3(USP9X):c.6991dup (p.Tyr2331fs)	Pathogenic
1703492	NM_001039591.3(USP9X):c.7188dup (p.Asn2397Ter)	Pathogenic
1710266	NM_001039591.3(USP9X):c.2281dup (p.Tyr761fs)	Pathogenic
2124584	NM_001039591.3(USP9X):c.1438_1439insCTGTT (p.Ser480fs)	Pathogenic
223094	NM_001039591.3(USP9X):c.2554C>T (p.Arg852Ter)	Pathogenic
223095	NM_001039591.3(USP9X):c.3028-2A>G	Pathogenic
223096	NM_001039591.3(USP9X):c.2644_2645insA (p.Arg882fs)	Pathogenic
223097	NM_001039591.3(USP9X):c.3763C>T (p.Gln1255Ter)	Pathogenic
223098	NM_001039591.3(USP9X):c.1111C>T (p.Arg371Ter)	Pathogenic
2293406	NM_001039591.3(USP9X):c.1957G>T (p.Glu653Ter)	Pathogenic
2498008	NM_001039591.3(USP9X):c.4972C>T (p.Arg1658Ter)	Pathogenic
2500934	NM_001039591.3(USP9X):c.6547del (p.Phe2182_Val2183insTer)	Pathogenic
2577814	NM_001039591.3(USP9X):c.6253C>T (p.Arg2085Cys)	Pathogenic
2628099	NM_001039591.3(USP9X):c.4135_4136del (p.Leu1379fs)	Pathogenic
2662428	NM_001039591.3(USP9X):c.2636G>A (p.Arg879Lys)	Pathogenic
2697482	NM_001039591.3(USP9X):c.2248C>T (p.Arg750Ter)	Pathogenic

SpliceAI

7466 predictions. Top by Δscore:

Variant	Effect	Δscore
X:41123465:TTGTA:T	acceptor_loss	1.0000
X:41123466:TGTA:T	acceptor_loss	1.0000
X:41123467:GTA:G	acceptor_loss	1.0000
X:41123468:TA:T	acceptor_loss	1.0000
X:41123721:TCAG:T	donor_loss	1.0000
X:41123722:CAG:C	donor_loss	1.0000
X:41123723:AGG:A	donor_loss	1.0000
X:41123724:GGTAG:G	donor_loss	1.0000
X:41123725:G:GA	donor_loss	1.0000
X:41123726:T:G	donor_loss	1.0000
X:41128993:A:AG	acceptor_gain	1.0000
X:41128994:A:G	acceptor_gain	1.0000
X:41128996:TAAGA:T	acceptor_loss	1.0000
X:41128997:A:AG	acceptor_gain	1.0000
X:41128997:AAGAC:A	acceptor_loss	1.0000
X:41128998:A:G	acceptor_gain	1.0000
X:41128999:G:GG	acceptor_gain	1.0000
X:41129021:A:AG	acceptor_gain	1.0000
X:41129021:AAT:A	acceptor_gain	1.0000
X:41129023:T:TA	acceptor_gain	1.0000
X:41129142:ACAG:A	donor_gain	1.0000
X:41129146:G:GA	donor_loss	1.0000
X:41129146:G:GG	donor_gain	1.0000
X:41129147:T:G	donor_loss	1.0000
X:41131533:AAGGG:A	donor_loss	1.0000
X:41131534:AGGGT:A	donor_loss	1.0000
X:41131535:GG:G	donor_gain	1.0000
X:41131536:GG:G	donor_gain	1.0000
X:41131537:G:A	donor_loss	1.0000
X:41131538:T:G	donor_loss	1.0000

AlphaMissense

16960 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:41129103:T:C	F67S	1.000
X:41129127:T:C	L75S	1.000
X:41131464:T:A	W84R	1.000
X:41131464:T:C	W84R	1.000
X:41131465:G:C	W84S	1.000
X:41131466:G:C	W84C	1.000
X:41131466:G:T	W84C	1.000
X:41131471:T:A	V86D	1.000
X:41131473:C:T	P87S	1.000
X:41131474:C:A	P87Q	1.000
X:41131474:C:G	P87R	1.000
X:41131477:T:A	V88D	1.000
X:41131495:T:C	L94S	1.000
X:41131504:T:C	L97P	1.000
X:41131515:G:C	A101P	1.000
X:41134758:T:C	F119S	1.000
X:41134773:T:C	L124P	1.000
X:41134797:T:C	L132P	1.000
X:41134802:G:C	D134H	1.000
X:41134803:A:T	D134V	1.000
X:41134820:T:A	W140R	1.000
X:41134820:T:C	W140R	1.000
X:41134821:G:C	W140S	1.000
X:41134822:G:C	W140C	1.000
X:41134822:G:T	W140C	1.000
X:41134823:A:G	K141E	1.000
X:41134833:T:A	I144N	1.000
X:41134833:T:C	I144T	1.000
X:41134833:T:G	I144S	1.000
X:41136832:T:C	L155P	1.000

dbSNP variants (sampled 300 via entrez): RS1000000385 (X:41191654 G>A), RS1000007934 (X:41118003 G>A), RS1000022631 (X:41182887 GGCT>G), RS1000037126 (X:41212150 C>G), RS1000057666 (X:41122274 T>C), RS1000172130 (X:41122559 G>A), RS1000174212 (X:41183100 G>A), RS1000174591 (X:41168554 T>A,G), RS1000181569 (X:41166667 A>G), RS1000192940 (X:41119052 T>G), RS1000260349 (X:41173461 C>T), RS1000348291 (X:41084132 C>T), RS1000351541 (X:41201557 A>G), RS1000386179 (X:41225482 A>T), RS1000438321 (X:41131241 A>G)

Disease associations

OMIM: gene MIM:300072 | disease phenotypes: MIM:300919, MIM:300968, MIM:117000, MIM:300928

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, X-linked 99, syndromic, female-restricted	Definitive	X-linked
intellectual disability, X-linked 99	Strong	X-linked
X-linked female restricted facial dysmorphism-short stature-choanal atresia-intellectual disability	Supportive	X-linked
non-syndromic X-linked intellectual disability	Supportive	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
X-linked syndromic intellectual disability	Definitive	XL

Mondo (10): intellectual disability, X-linked 99 (MONDO:0010487), intellectual disability, X-linked 99, syndromic, female-restricted (MONDO:0010502), neurodevelopmental disorder (MONDO:0700092), intellectual disability (MONDO:0001071), hyperpigmentation of the skin (MONDO:0019289), congenital myopathy (MONDO:0019952), hereditary ataxia (MONDO:0100309), intellectual disability, X-linked 101 (MONDO:0010489), X-linked female restricted facial dysmorphism-short stature-choanal atresia-intellectual disability (MONDO:0018821), non-syndromic X-linked intellectual disability (MONDO:0019181)

Orphanet (5): X-linked non-syndromic intellectual disability (Orphanet:777), Hyperpigmentation of the skin (Orphanet:79375), Congenital myopathy (Orphanet:97245), Hereditary ataxia (Orphanet:183518), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

117 total (30 of 117 shown, HPO-id order):

HPO	Term
HP:0000047	Hypospadias
HP:0000086	Ectopic kidney
HP:0000110	Renal dysplasia
HP:0000119	Abnormality of the genitourinary system
HP:0000126	Hydronephrosis
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000193	Bifid uvula
HP:0000212	Gingival overgrowth
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000248	Brachycephaly
HP:0000319	Smooth philtrum
HP:0000324	Facial asymmetry
HP:0000341	Narrow forehead
HP:0000343	Long philtrum
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000414	Bulbous nose
HP:0000431	Wide nasal bridge
HP:0000448	Prominent nose
HP:0000453	Choanal atresia
HP:0000454	Flared nostrils
HP:0000478	Abnormality of the eye
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000506	Telecanthus
HP:0000518	Cataract

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST003720_6	Migraine	2.000000e-08

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
C531684	Hereditary spinal ataxia (supp.)
C564490	Mental Retardation, X-Linked Nonsyndromic (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2406899 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 81 (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
CHEMBL4650332	ETAVOPIVAT	2	81

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

Binding affinities (BindingDB)

3 measured of 6 human assays (6 total across all organisms); most potent 3 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
Preparation of (S)-3-hydroxy-2-phenyl-1-(1’-(pyridin-2-ylsulfonyl)-1’,4’-dihydro-2H,2’H-[3.3’-diazetidinylidene]-1(4H)-yl)propan-1-one	IC50	200 nM	US-20250145635: COMPOUND CONTAINING BIS(AZANYLYLIDENE) SULFONYL STRUCTURE AND USE THEREOF IN MEDICINE
Preparation of 1-(1’-((4-(difluoromethoxy)phenyl)sulfonyl)-1’,4’-dihydro-2H,2’H-[3,3’-diazetidinylidene]-1(4H)-yl)-3-hydroxy-2-phenylpropan-1-one	IC50	200 nM	US-20250145635: COMPOUND CONTAINING BIS(AZANYLYLIDENE) SULFONYL STRUCTURE AND USE THEREOF IN MEDICINE
Preparation of (S)-1-(1’-(benzo[d]thiazol-6-ylsulfonyl)-1’,4’-dihydro-2H,2’H-[3,3’-diazetidinylidene]-1(4H)-yl)-3-hydroxy-2-phenylpropan-1-one	IC50	650 nM	US-20250145635: COMPOUND CONTAINING BIS(AZANYLYLIDENE) SULFONYL STRUCTURE AND USE THEREOF IN MEDICINE

ChEMBL bioactivities

405 potent at pChembl≥5 of 406 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	IC50	1	nM	CHEMBL5087604
9.00	IC50	1	nM	CHEMBL5081543
9.00	IC50	1	nM	CHEMBL5089843
9.00	IC50	1	nM	CHEMBL5089941
9.00	IC50	1	nM	CHEMBL5093513
9.00	IC50	1	nM	CHEMBL5076738
9.00	IC50	1	nM	CHEMBL5093019
9.00	IC50	1	nM	CHEMBL5070827
9.00	IC50	1	nM	CHEMBL5074124
9.00	IC50	1	nM	CHEMBL5084410
9.00	IC50	1	nM	CHEMBL5079020
9.00	IC50	1	nM	CHEMBL5086426
9.00	IC50	1	nM	CHEMBL5071051
9.00	IC50	1	nM	CHEMBL5076417
9.00	IC50	1	nM	CHEMBL5080931
9.00	IC50	1	nM	CHEMBL5090630
9.00	IC50	1	nM	CHEMBL5088777
9.00	IC50	1	nM	CHEMBL5074944
9.00	IC50	1	nM	CHEMBL5071991
9.00	IC50	1	nM	CHEMBL5078314
9.00	IC50	1	nM	CHEMBL5082460
9.00	IC50	1	nM	CHEMBL5075259
9.00	IC50	1	nM	CHEMBL5089140
9.00	IC50	1	nM	CHEMBL5085499
9.00	IC50	1	nM	CHEMBL5087360
9.00	IC50	1	nM	CHEMBL5076220
9.00	IC50	1	nM	CHEMBL5075503
9.00	IC50	1	nM	CHEMBL5070846
9.00	IC50	1	nM	CHEMBL5071382
9.00	IC50	1	nM	CHEMBL5076545
9.00	IC50	1	nM	CHEMBL5075632
9.00	IC50	1	nM	CHEMBL5083364
9.00	IC50	1	nM	CHEMBL5087937
9.00	IC50	1	nM	CHEMBL5077384
9.00	IC50	1	nM	CHEMBL5075420
9.00	IC50	1	nM	CHEMBL5079385
9.00	IC50	1	nM	CHEMBL5077487
9.00	IC50	1	nM	CHEMBL5078625
9.00	IC50	1	nM	CHEMBL5090564
9.00	IC50	1	nM	CHEMBL5077695
9.00	IC50	1	nM	CHEMBL5072669
9.00	IC50	1	nM	CHEMBL5071913
9.00	IC50	1	nM	CHEMBL5076148
9.00	IC50	1	nM	CHEMBL5075117
9.00	IC50	1	nM	CHEMBL5077308
9.00	IC50	1	nM	CHEMBL5072768
9.00	IC50	1	nM	CHEMBL5077098
9.00	IC50	1	nM	CHEMBL5072962
9.00	IC50	1	nM	CHEMBL5083615
9.00	IC50	1	nM	CHEMBL5082668

PubChem BioAssay actives

5 with measured affinity, of 48 total; 3 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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149959: Binding affinity to human USP9X incubated for 45 mins by Kinobead based pull down assay	kd	0.0603	uM
(E)-3-(6-bromo-2-pyridinyl)-2-cyano-N-[(1S)-1-phenylbutyl]prop-2-enamide	1930829: Inhibition of USP9x (unknown origin)	ic50	2.5000	uM
(Z)-3-(6-bromo-2-pyridinyl)-N-[[3-[[[(Z)-3-(6-bromo-2-pyridinyl)-2-cyanoprop-2-enoyl]amino]methyl]phenyl]methyl]-2-cyanoprop-2-enamide	1069730: Inhibition of human recombinant N-terminal His6-Smt3-fusion-tagged Usp9x catalytic domain expressed in Escherichia coli using Ub-AMC as substrate incubated for 30 mins prior to substrate addition by fluorescence assay	ic50	2.5000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, decreases methylation	3
bisphenol A	decreases expression	2
sodium arsenite	decreases expression, increases abundance, increases expression	2
potassium chromate(VI)	affects cotreatment, decreases expression	2
entinostat	increases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
Tretinoin	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
AZD5991	decreases ubiquitination, affects binding, decreases reaction, affects cotreatment	1
tapotoclax	affects binding, decreases reaction, affects cotreatment, decreases ubiquitination	1
2,4,6-tribromophenol	decreases expression	1
methylmercuric chloride	decreases expression	1
pyrogallol 1,3-dimethyl ether	decreases expression, increases expression, affects cotreatment	1
trichostatin A	decreases expression	1
arsenite	affects binding, decreases reaction	1
methylparaben	increases expression	1
butyraldehyde	decreases expression	1
manganese chloride	decreases expression, increases abundance	1
nickel sulfate	decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
tamibarotene	affects expression	1
chromium hexavalent ion	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1

ChEMBL screening assays

41 unique, capped per target: 41 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2411907	Binding	Inhibition of USP9x in human Z138 cells after 1 hr by immunoblotting analysis	Vialinin A is a ubiquitin-specific peptidase inhibitor. — Bioorg Med Chem Lett

Cellosaurus cell lines

5 cell lines: 4 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2KS	Abcam HeLa USP9X KO	Cancer cell line	Female
CVCL_D6BG	HyCyte HEK293 KO-hUSP9X	Transformed cell line	Female
CVCL_KU20	HeLa SilenciX USP9X	Cancer cell line	Female
CVCL_TX16	HAP1 USP9X (-) 1	Cancer cell line	Male
CVCL_TX17	HAP1 USP9X (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

299 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,
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
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
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
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
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
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays