CBX4

Summary

CBX4 (chromobox 4, HGNC:1554) is a protein-coding gene on chromosome 17q25.3, encoding E3 SUMO-protein ligase CBX4 (O00257). E3 SUMO-protein ligase that catalyzes sumoylation of target proteins by promoting the transfer of SUMO from the E2 enzyme to the substrate.

Enables SUMO binding activity; SUMO ligase activity; and enzyme binding activity. Involved in negative regulation of transcription by RNA polymerase II. Located in nuclear body. Part of PRC1 complex. Implicated in hepatocellular carcinoma. Biomarker of hepatocellular carcinoma.

Source: NCBI Gene 8535 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 91 total
• Druggable target: yes
• MANE Select transcript: NM_003655

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1554
Approved symbol	CBX4
Name	chromobox 4
Location	17q25.3
Locus type	gene with protein product
Status	Approved
Aliases	hPC2, PC2, NBP16
Ensembl gene	ENSG00000141582
Ensembl biotype	protein_coding
OMIM	603079
Entrez	8535

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 retained_intron

ENST00000269397, ENST00000448310, ENST00000494546, ENST00000495122, ENST00000961345

RefSeq mRNA: 1 — MANE Select: NM_003655 NM_003655

CCDS: CCDS32758

Canonical transcript exons

ENST00000269397 — 5 exons

Exon	Start	End
ENSE00000949908	79837837	79837902
ENSE00001381165	79833156	79835395
ENSE00001828861	79839183	79839440
ENSE00002480739	79835646	79835712
ENSE00003535119	79839011	79839054

Expression profiles

Bgee: expression breadth ubiquitous, 264 present calls, max score 96.37.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 50.6081 / max 1740.3528, expressed in 1825 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
168580	44.9102	1820
168581	5.6979	1694

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
upper leg skin	UBERON:0004262	96.37	gold quality
penis	UBERON:0000989	95.79	gold quality
mucosa of paranasal sinus	UBERON:0005030	95.39	gold quality
skin of hip	UBERON:0001554	94.63	gold quality
corpus epididymis	UBERON:0004359	94.34	gold quality
nipple	UBERON:0002030	94.29	gold quality
gingival epithelium	UBERON:0001949	93.83	gold quality
gingiva	UBERON:0001828	93.82	gold quality
oral cavity	UBERON:0000167	93.74	gold quality
mammalian vulva	UBERON:0000997	93.67	gold quality
pigmented layer of retina	UBERON:0001782	93.67	gold quality
lateral nuclear group of thalamus	UBERON:0002736	93.67	gold quality
esophagus squamous epithelium	UBERON:0006920	93.64	gold quality
inferior vagus X ganglion	UBERON:0005363	93.35	gold quality
trabecular bone tissue	UBERON:0002483	93.23	gold quality
amniotic fluid	UBERON:0000173	93.18	gold quality
seminal vesicle	UBERON:0000998	92.97	gold quality
ventral tegmental area	UBERON:0002691	92.84	gold quality
lower lobe of lung	UBERON:0008949	92.82	gold quality
entorhinal cortex	UBERON:0002728	92.74	gold quality
pylorus	UBERON:0001166	92.55	gold quality
caput epididymis	UBERON:0004358	92.12	gold quality
heart right ventricle	UBERON:0002080	92.07	gold quality
subthalamic nucleus	UBERON:0001906	91.86	gold quality
cardia of stomach	UBERON:0001162	91.53	gold quality
pharyngeal mucosa	UBERON:0000355	91.44	gold quality
lateral globus pallidus	UBERON:0002476	91.38	gold quality
parietal lobe	UBERON:0001872	91.35	gold quality
postcentral gyrus	UBERON:0002581	91.27	gold quality
superficial temporal artery	UBERON:0001614	91.00	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.43
E-MTAB-4850	no	57.68

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

79 targeting CBX4, 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-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197

Literature-anchored findings (GeneRIF, showing 40)

• Pc2 dramatically enhances CtBP sumoylation. Pc2 is a SUMO E3, and Polycomb Group bodies may be sumoylation centers. (PMID:12679040)
• polycomb group (PcG) protein HPC2, which functions as a transcriptional suppressor, is a candidate of KyoT2-binding proteins (PMID:15710417)
• SIP1 sumoylation by Pc2 attenuates transcriptional repression of E-cadherin (PMID:16061479)
• Pc2 binds to and colocalizes with homeodomain interacting protein kinase 2 (HIPK2) and serves as a SUMO E3 ligase for this kinase. (PMID:17018294)
• The Endoplasmic reticulum-associated degradation (ERAD) machinery may thus be important for autosomal dominant polycystic kidney disease pathogenesis because the regulation of PC2 expression by the ERAD pathway is altered by mutations in PC2. (PMID:18178578)
• Results show that DNA methyltransferase 3B enhances polycomb protein 2-mediated transcriptional repression of FGFR3, and suggest that DNMT3B is a co-repressor of hPc2 in inducing transcriptional repression independent of DNA methylation. (PMID:18567530)
• A phage display screen using the N-terminus of JARID1B as bait identified one of the JARID1B interacting proteins, namely PcG protein (Polycomb group) hPc2. (PMID:19336002)
• Huntingtin is a novel stimulator of polycomb repressive complex 2. (PMID:19933700)
• the hPc2-induced SUMOylation of alpha-synuclein could function as a cytoprotector by increasing alpha-synuclein aggregate formation within fibroblast cells. (PMID:21256122)
• 14-3-3 protein binding to chromobox homolog 4 (CBX4) appears to modulate the interaction between CBX4 and the BMI1/PCGF components of polycomb recessive complex 1, but has no effect on CBX4-RING1/RNF2 interaction (PMID:21282530)
• Data show that PRC2 can integrate information provided by pre-existing histone modifications to accurately tune its enzymatic activity within a particular chromatin context. (PMID:21549310)
• plays role in regulation of epidermal stem cell proliferation and senescence (PMID:21885019)
• High Polycomb repressive complex protein is associated with mesothelioma. (PMID:22028491)
• Pc2, methylation controls the protein’s interaction with two distinct ncRNAs, TUG1 and NEAT2, which results in the exclusive subnuclear localization of methylated and unmethylated Pc2 in Polycomb bodies and interchromatin granules, respectively. (PMID:22078878)
• ASXL1 associates with the PRC2 and loss of ASXL1 in vivo collaborates with NRASG12D to promote myeloid leukemogenesis. (PMID:22897849)
• High cytoplasmic expression of CBX4 is associated with hepatocellular carcinoma. (PMID:23943028)
• our findings demonstrate that Cbx4 plays a critical role in tumor angiogenesis by governing HIF-1alpha protein (PMID:24434214)
• The presence of CBX4-GFP in the same focus had a minor impact on BMI1 and RING1 recovery kinetics. (PMID:24460908)
• Role of Cbx4 in migration and metastasis of a metastatic hepatocellular carcinoma cell line. Results show that Cbx4 overexpression increases the in vitro vessel formation of vascular endothelial cells in its SUMO interaction motifs-dependent manner. (PMID:24838576)
• Cbx4 is an independent prognostic factor for HCC patients, and the patients with high Cbx4 expression should receive postoperative TACE treatment to improve their survival (PMID:25766328)
• provide evidence to show that CBX4 may serve as a tumor suppressor in colorectal carcinoma by recruiting HDAC3 to the Runx2 promoter to impede Runx2 expression (PMID:27864346)
• Data show that SUMO E3 ligase CBX4 sumoylates subpopulation of CtIP to regulate recruitment to breaks and resection. (PMID:28740167)
• Data show that USP26 interacts with PRC1 components chromobox (CBX)-containing proteins CBX4 and CBX6. (PMID:28839133)
• Data suggest that CBX4 expression is up-regulated in breast cancer and is correlated with unfavorable overall survival; CBX4 promotes cell growth and migration via transcriptionally suppressing expression of miR137 to trigger Notch1 signaling pathway. (CBX4 = chromobox homolog 4; miR137 = microRNA 137; Notch1 = neurogenic locus notch homolog protein-1) (PMID:29229426)
• Results identify a modifying enzyme for Prdm16, and they demonstrate a central role of Cbx4 in the control of Prdm16 stability and white fat browning. (PMID:29539416)
• CBX4 is up-regulated in breast cancer tissues and while its over-expression promotes cell proliferation, its knockdown suppresses cell proliferation in breast cancer cells. Furthermore, CBX4 mediates miR-129-5p-induced inhibition of cell proliferation and negatively correlates with the expression of miR-129-5p expression. (PMID:29940764)
• role of CBX4 in maintaining cellular homeostasis in mesenchymal stem cells (PMID:30917318)
• findings suggest that CBX4 rs2289728 and CBX7 rs139394 are protective SNPs against HCC. The two SNPs may reduce the risk of HCC while suppressing the expression of CBX4 and CBX7. (PMID:31211140)
• This is the evidence supporting the interaction between GRM4 and CBX4, which could inhibit the malignant behavior of osteosarcoma cells through the GRM4/CBX4/HIF-1alpha signaling pathway (PMID:31581881)
• CBX4 promotes the proliferation and metastasis via regulating BMI-1 in lung cancer. (PMID:31724308)
• Chromobox homolog 4 (CBX4) is overexpressed in osteosarcoma cell lines and tissues. CBX4 promotes metastasis by transcriptionally up-regulating Runx2 via the recruitment of GCN5 to the Runx2 promoter. The phosphorylation of CBX4 at T437 by casein kinase 1alpha (CK1alpha) facilitates its ubiquitination at both K178 and K280 and subsequent degradation by CHIP, and this phosphorylation of CBX4 could be reduced by TNFalpha. (PMID:32111827)
• Circular RNA hsa_circ_0008039 promotes proliferation, migration and invasion of breast cancer cells through upregulating CBX4 via sponging miR-515-5p. (PMID:32141558)
• SUMO E3 ligase CBX4 regulates hTERT-mediated transcription of CDH1 and promotes breast cancer cell migration and invasion. (PMID:32926159)
• Chromobox 4 facilitates tumorigenesis of lung adenocarcinoma through the Wnt/beta-catenin pathway. (PMID:33387960)
• Long intergenic noncoding RNA00265 promotes proliferation of gastric cancer via the microRNA-144-3p/Chromobox 4 axis. (PMID:33464142)
• The predictive potential of genetic single nucleotide polymorphisms in CBX4 for hepatocellular carcinoma survival. (PMID:34856763)
• CBX4-dependent regulation of HDAC3 nuclear translocation reduces Bmp2-induced osteoblastic differentiation and calcification in adamantinomatous craniopharyngioma. (PMID:34980138)
• CBX4 Regulates Replicative Senescence of WI-38 Fibroblasts. (PMID:35251476)
• CBX4 Regulates Long-Form Thymic Stromal Lymphopoietin-mediated Airway Inflammation through SUMOylation in House Dust Mite-induced Asthma. (PMID:35358396)
• MiR-507 inhibits the progression of gastric carcinoma via targeting CBX4-mediated activation of Wnt/beta-catenin and HIF-1alpha pathways. (PMID:35819589)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cbx4	ENSDARG00000099441
mus_musculus	Cbx4	ENSMUSG00000039989
rattus_norvegicus	Cbx4	ENSRNOG00000063043
caenorhabditis_elegans		WBGENE00001995
caenorhabditis_elegans		WBGENE00007615

Paralogs (8): CBX5 (ENSG00000094916), CBX7 (ENSG00000100307), CBX1 (ENSG00000108468), CBX3 (ENSG00000122565), CBX8 (ENSG00000141570), CBX2 (ENSG00000173894), CBX6 (ENSG00000183741), NPTXR (ENSG00000221890)

Protein

Protein identifiers

E3 SUMO-protein ligase CBX4 — O00257 (reviewed: O00257)

Alternative names: Chromobox protein homolog 4, Polycomb 2 homolog

All UniProt accessions (4): A0A0S2Z5B2, O00257, F8WCW6, I3L4F1

UniProt curated annotations — full annotation on UniProt →

Function. E3 SUMO-protein ligase that catalyzes sumoylation of target proteins by promoting the transfer of SUMO from the E2 enzyme to the substrate. Also acts as a histone reader, which specifically recognizes and binds histone H3 trimethylated at ‘Lys-9’ and ‘Lys-27’ (H3K9me3 and H3K27me3, respectively) via its chromo domain. Catalyzes sumoylation of HNRNPK, a p53/TP53 transcriptional coactivator, hence indirectly regulates p53/TP53 transcriptional activation resulting in p21/CDKN1A expression. Acts as a regulator of brown adipocyte differentiation by mediating sumoylation of PRDM16, thereby preventing PRDM16 ubiquitination and degradation. Monosumoylates ZNF131. Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A ‘Lys-119’, rendering chromatin heritably changed in its expressibility. Plays a role in the lineage differentiation of the germ layers in embryonic development.

Subunit / interactions. Component of a PRC1-like complex. The composition of the PRC1 complex differs between the PRC1 complex in pluripotent embryonic stem cells containing RNF2, CBX7 and PCGF2, and the PRC1 complex in differentiating cells containing RNF2, CBX2, CBX4 and BMI1. Interacts with SUV39H1 and HIPK2. Interacts with CSNK2B. Interacts with PRDM1. Interacts with CHTOP. Interacts with SUMO1P1/SUMO5. Associates with single-stranded RNA (ssRNA).

Subcellular location. Nucleus. Nucleus speckle.

Tissue specificity. Ubiquitous.

Post-translational modifications. Ubiquitinated. Ubiquitination regulates the function of the Polycomb group (PcG) multiprotein PRC1-like complex. Deubiquitinated by USP26. Phosphorylated on Thr-497 by HIPK2 upon DNA damage. This phosphorylation stimulates E3 SUMO-protein ligase activity and promotes sumoylation on Lys-494, as well as sumoylation of other target proteins, such as HNRNPK.

Domain organisation. The polyhistidine repeat may act as a targeting signal to nuclear speckles.

Pathway. Protein modification; protein sumoylation.

Miscellaneous. The human orthologs of the Drosophila Polycomb group protein Pc are CBX2, CBX4, CBX6, CBX7 and CBX8. These show distinct nuclear localizations, contribute differently to transcriptional repression, and appear to be part of distinct PRC1-like protein complexes. The hPRC-H complex purified in PubMed:12167701 probably presents a mixture of different complexes containing different Polycomb group proteins.

Isoforms (2)

UniProt ID	Names	Canonical?
O00257-1	1	yes
O00257-3	2

RefSeq proteins (1): NP_003646* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000953	Chromo/chromo_shadow_dom	Domain
IPR016197	Chromo-like_dom_sf	Homologous_superfamily
IPR017984	Chromo_dom_subgr	Domain
IPR023779	Chromodomain_CS	Conserved_site
IPR023780	Chromo_domain	Domain
IPR033773	CBX7_C	Conserved_site
IPR043531	CBX4	Family

Pfam: PF00385, PF17218

UniProt features (56 total): cross-link 21, region of interest 8, sequence conflict 6, compositionally biased region 4, modified residue 4, mutagenesis site 4, strand 3, helix 3, chain 1, domain 1, splice variant 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3I8Z	X-RAY DIFFRACTION	1.51
5EPL	X-RAY DIFFRACTION	1.81
2K28	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00257-F1	55.01	0.11

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 (25): 149, 182, 467, 497, 77, 106, 114, 125, 149, 157, 167, 178, 191, 205, 212, 223, 249, 268, 278, 280 …

Mutagenesis-validated functional residues (4):

Position	Phenotype
16	reduced interaction with h3c15, h3c1 and rnf2.
434	abolishes interaction with ywhaz and ywhae; impairs interaction with pcgf6 and bmi1; no effect on interaction with rnf2.
494	no effect on znf131 sumoylation.
497	small decrease in znf131 sumoylation.

Function

Pathways and Gene Ontology

Reactome pathways

24 pathways

ID	Pathway
R-HSA-2559580	Oxidative Stress Induced Senescence
R-HSA-3108214	SUMOylation of DNA damage response and repair proteins
R-HSA-3899300	SUMOylation of transcription cofactors
R-HSA-4551638	SUMOylation of chromatin organization proteins
R-HSA-4570464	SUMOylation of RNA binding proteins
R-HSA-4655427	SUMOylation of DNA methylation proteins
R-HSA-8939243	RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known
R-HSA-8943724	Regulation of PTEN gene transcription
R-HSA-9976102	Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-162582	Signal Transduction
R-HSA-212436	Generic Transcription Pathway
R-HSA-2262752	Cellular responses to stress
R-HSA-2559583	Cellular Senescence
R-HSA-2990846	SUMOylation
R-HSA-3108232	SUMO E3 ligases SUMOylate target proteins
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification
R-HSA-6807070	PTEN Regulation
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8878171	Transcriptional regulation by RUNX1
R-HSA-8953897	Cellular responses to stimuli
R-HSA-9006925	Intracellular signaling by second messengers

MSigDB gene sets: 377 (showing top): GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, BENPORATH_ES_WITH_H3K27ME3, TGCGCANK_UNKNOWN, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, BROWNE_HCMV_INFECTION_8HR_UP, TTTGTAG_MIR520D, GOBP_POSITIVE_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, TATTATA_MIR374, LANG_MYB_FAMILY_TARGETS, GOBP_REGULATION_OF_BROWN_FAT_CELL_DIFFERENTIATION, AATGGAG_MIR136

GO Biological Process (8): negative regulation of transcription by RNA polymerase II (GO:0000122), protein sumoylation (GO:0016925), negative regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032435), negative regulation of apoptotic process (GO:0043066), negative regulation of DNA-templated transcription (GO:0045892), protein stabilization (GO:0050821), positive regulation of brown fat cell differentiation (GO:0090336), chromatin organization (GO:0006325)

GO Molecular Function (12): transcription cis-regulatory region binding (GO:0000976), chromatin binding (GO:0003682), transcription corepressor activity (GO:0003714), single-stranded RNA binding (GO:0003727), SUMO transferase activity (GO:0019789), enzyme binding (GO:0019899), SUMO binding (GO:0032183), phosphoprotein binding (GO:0051219), histone H3K27me3 reader activity (GO:0061628), SUMO ligase activity (GO:0061665), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), nuclear body (GO:0016604), nuclear speck (GO:0016607), PcG protein complex (GO:0031519), PRC1 complex (GO:0035102)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
SUMO E3 ligases SUMOylate target proteins	5
Cellular Senescence	1
Transcriptional regulation by RUNX1	1
PTEN Regulation	1
Differentiation of T cells	1
Intracellular signaling by second messengers	1
RNA Polymerase II Transcription	1
Cellular responses to stimuli	1
Cellular responses to stress	1
Post-translational protein modification	1
SUMOylation	1
Metabolism of proteins	1
PIP3 activates AKT signaling	1
Gene expression (Transcription)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative regulation of DNA-templated transcription	2
binding	2
protein binding	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
peptidyl-lysine modification	1
protein modification by small protein conjugation	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
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
regulation of protein stability	1
positive regulation of fat cell differentiation	1
brown fat cell differentiation	1
regulation of brown fat cell differentiation	1
cellular component organization	1
transcription regulatory region nucleic acid binding	1
sequence-specific double-stranded DNA binding	1
transcription coregulator activity	1
RNA binding	1
ubiquitin-like protein transferase activity	1
ubiquitin-like protein binding	1
histone H3 reader activity	1
SUMO transferase activity	1
ubiquitin-like protein ligase activity	1
catalytic activity	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
nucleoplasm	1
intracellular membraneless organelle	1
nuclear ribonucleoprotein granule	1
nuclear protein-containing complex	1
nuclear ubiquitin ligase complex	1

Protein interactions and networks

STRING

1313 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CBX4	BMI1	P35226	991
CBX4	R4GMX3	R4GMX3	991
CBX4	RING1	Q06587	974
CBX4	CBX8	Q9HC52	966
CBX4	RNF2	Q99496	962
CBX4	CBX2	Q14781	951
CBX4	PHC1	P78364	891
CBX4	CBX7	O95931	875
CBX4	CBX6	O95503	861
CBX4	L3MBTL1	Q9Y468	805
CBX4	PCGF2	P35227	801
CBX4	PHC3	Q8NDX5	800
CBX4	PHC2	Q8IXK0	753
CBX4	SCML2	Q9UQR0	740
CBX4	EZH2	Q15910	686

IntAct

158 interactions, top by confidence:

A	B	Type	Score
BMI1	CBX4	psi-mi:“MI:0914”(association)	0.900
BMI1	CBX4	psi-mi:“MI:0915”(physical association)	0.900
PCGF2	CBX4	psi-mi:“MI:0914”(association)	0.840
PHC1	CBX4	psi-mi:“MI:0914”(association)	0.790
RING1	CBX4	psi-mi:“MI:0914”(association)	0.730
CBX4	CTBP1	psi-mi:“MI:0915”(physical association)	0.700
CBX4	CTBP1	psi-mi:“MI:0403”(colocalization)	0.700
CTBP1	CBX4	psi-mi:“MI:0914”(association)	0.700
CBX8	CBX4	psi-mi:“MI:0914”(association)	0.670
CBX4	CBX8	psi-mi:“MI:0915”(physical association)	0.670
HIF1A	CBX4	psi-mi:“MI:0914”(association)	0.670
HIF1A	CBX4	psi-mi:“MI:0915”(physical association)	0.670
CBX4	HIF1A	psi-mi:“MI:0915”(physical association)	0.670

BioGRID (377): CBX4 (Protein-peptide), CBX4 (Affinity Capture-Western), CBX4 (Affinity Capture-MS), CBX4 (Affinity Capture-MS), CBX4 (Affinity Capture-MS), CBX4 (Affinity Capture-MS), CBX4 (Affinity Capture-MS), CBX4 (Two-hybrid), CBX4 (Proximity Label-MS), BMI1 (Affinity Capture-MS), PHC1 (Affinity Capture-MS), PHC2 (Affinity Capture-MS), H3F3A (Affinity Capture-MS), HELLS (Affinity Capture-MS), MYL6 (Affinity Capture-MS)

ESM2 similar proteins: A2VDR9, A5PKG8, A6NMT0, A7MB40, A8MUI8, E2R9X2, O00257, O15353, O43151, O55187, P19419, P30658, P48382, P52950, P59598, Q03989, Q0GGX2, Q13029, Q14781, Q28BT7, Q2MHN3, Q32MQ0, Q32N19, Q3SWY1, Q3TEI4, Q3U108, Q3UHR0, Q497V6, Q568E2, Q571I4, Q5JPB2, Q5NSW5, Q5TGY3, Q61818, Q6PAL7, Q6ZRI6, Q7TSH3, Q7Z5J4, Q811R2, Q86YN6

Diamond homologs: G5EDE2, G5EET5, O00257, O43463, O54864, O55187, O95503, O95931, P05205, P23198, P26017, P30658, P34618, P45973, P60889, P83916, P83917, Q10103, Q13185, Q14781, Q28CQ7, Q2NL30, Q32PH7, Q339W7, Q4R3E0, Q5F3W5, Q5R6X7, Q5RB81, Q61686, Q6DGD3, Q7JXA8, Q8N8U2, Q8VDS3, Q944N1, Q946J8, Q9D5D8, Q9DBY5, Q9EQQ0, Q9H5I1, Q9HC52

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
CBX4	“down-regulates activity”	ZEB2	sumoylation
KDM5B	“up-regulates activity”	CBX4	binding
CSNK1A1	“down-regulates quantity by destabilization”	CBX4	phosphorylation
STUB1	“down-regulates quantity by destabilization”	CBX4	ubiquitination
HIPK2	“up-regulates activity”	CBX4	phosphorylation
CBX4	“down-regulates quantity by destabilization”	ZEB2	sumoylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 93 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
SUMOylation of DNA methylation proteins	10	113.9×	3e-17
Activation of BAD and translocation to mitochondria	6	77.4×	3e-09
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	68.3×	7e-09
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	68.3×	7e-09
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	12	61.1×	5e-17
SUMOylation of transcription cofactors	13	53.5×	3e-17
Activation of BH3-only proteins	6	50.5×	4e-08
SUMOylation of RNA binding proteins	11	44.4×	5e-14

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of proteasomal ubiquitin-dependent protein catabolic process	5	25.7×	2e-04
protein targeting	5	23.5×	2e-04
chromatin remodeling	12	11.2×	3e-07
intracellular protein localization	7	9.4×	7e-04
regulation of cell cycle	7	6.7×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	79
Likely benign	0
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

702 predictions. Top by Δscore:

Variant	Effect	Δscore
17:79835394:ACC:A	acceptor_loss	1.0000
17:79835709:TTCC:T	acceptor_gain	1.0000
17:79835710:TCC:T	acceptor_gain	1.0000
17:79835711:CC:C	acceptor_gain	1.0000
17:79835711:CCC:C	acceptor_gain	1.0000
17:79835712:CC:C	acceptor_gain	1.0000
17:79835712:CCT:C	acceptor_loss	1.0000
17:79835713:C:CC	acceptor_gain	1.0000
17:79835713:C:T	acceptor_gain	1.0000
17:79835713:CTG:C	acceptor_loss	1.0000
17:79835714:T:G	acceptor_loss	1.0000
17:79835717:G:C	acceptor_gain	1.0000
17:79835717:G:GC	acceptor_gain	1.0000
17:79837832:CTCA:C	donor_loss	1.0000
17:79837833:TCA:T	donor_loss	1.0000
17:79837834:CA:C	donor_loss	1.0000
17:79837836:C:CT	donor_loss	1.0000
17:79837899:ATATC:A	acceptor_loss	1.0000
17:79837901:ATCT:A	acceptor_loss	1.0000
17:79837902:TCTTG:T	acceptor_loss	1.0000
17:79837903:C:CC	acceptor_gain	1.0000
17:79837903:C:T	acceptor_loss	1.0000
17:79837904:T:C	acceptor_gain	1.0000
17:79837904:T:G	acceptor_loss	1.0000
17:79837904:T:TC	acceptor_gain	1.0000
17:79837907:C:CT	acceptor_gain	1.0000
17:79839007:TTA:T	donor_loss	1.0000
17:79839009:A:AC	donor_gain	1.0000
17:79839010:C:CT	donor_gain	1.0000
17:79839177:CCCTA:C	donor_loss	1.0000

AlphaMissense

3672 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:79833977:C:A	K555N	1.000
17:79833977:C:G	K555N	1.000
17:79833981:A:G	F554S	1.000
17:79833987:A:T	V552D	1.000
17:79833993:A:G	L550P	1.000
17:79833993:A:T	L550H	1.000
17:79834005:G:A	T546I	1.000
17:79834008:A:T	V545D	1.000
17:79834011:T:A	D544V	1.000
17:79834011:T:C	D544G	1.000
17:79834011:T:G	D544A	1.000
17:79834012:C:A	D544Y	1.000
17:79834012:C:G	D544H	1.000
17:79834014:G:A	T543I	1.000
17:79834017:A:C	I542S	1.000
17:79834017:A:G	I542T	1.000
17:79834017:A:T	I542N	1.000
17:79834023:A:T	I540K	1.000
17:79834848:A:T	V265E	1.000
17:79834851:A:C	I264S	1.000
17:79834851:A:T	I264N	1.000
17:79834854:A:T	V263E	1.000
17:79834857:A:C	I262S	1.000
17:79834857:A:G	I262T	1.000
17:79834857:A:T	I262N	1.000
17:79834860:C:G	R261P	1.000
17:79834861:G:T	R261S	1.000
17:79834863:C:A	G260V	1.000
17:79834863:C:T	G260E	1.000
17:79834864:C:G	G260R	1.000

dbSNP variants (sampled 300 via entrez): RS1000012052 (17:79840693 C>A), RS1000043234 (17:79840553 G>A,T), RS1000075979 (17:79840295 G>A), RS1000429929 (17:79835518 G>A,C,T), RS1000922342 (17:79835781 T>A,C,G), RS1001155442 (17:79840811 C>T), RS1001267647 (17:79840743 G>A), RS1001431018 (17:79835955 C>A,T), RS1001670894 (17:79834613 G>A,C), RS1001771738 (17:79840606 T>C), RS1002314776 (17:79836009 C>T), RS1002773666 (17:79836184 G>A,C), RS1002918613 (17:79833197 G>A,T), RS1004062848 (17:79838808 G>A), RS1004561759 (17:79839910 C>T)

Disease associations

OMIM: gene MIM:603079 | disease phenotypes: MIM:602723

GenCC curated gene-disease

Mondo (2): psoriasis 2 (MONDO:0011269), pityriasis rubra pilaris (MONDO:0100017)

Orphanet (1): Pityriasis rubra pilaris (Orphanet:2897)

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST002549_3	Response to serotonin reuptake inhibitors in major depressive disorder (plasma drug and metabolite levels)	2.000000e-07
GCST003081_5	Glucocorticoid-induced osteonecrosis (age 10 years and older)	3.000000e-06
GCST010703_16	Brain morphology (MOSTest)	1.000000e-09
GCST010796_4577	Electrocardiogram morphology (amplitude at temporal datapoints)	7.000000e-09
GCST010796_4578	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST010796_4579	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-08
GCST010796_4580	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005658	response to selective serotonin reuptake inhibitor
EFO:0004346	neuroimaging measurement
EFO:0004327	electrocardiography

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D010916	Pityriasis Rubra Pilaris	C17.800.859.600.685

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3232685 (SINGLE PROTEIN)

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

ChEMBL bioactivities

36 potent at pChembl≥5 of 43 total, top 35 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.57	Kd	26.7	nM	CHEMBL5715919
7.21	IC50	62	nM	CHEMBL3972289
7.12	IC50	75	nM	CHEMBL3958557
7.12	IC50	75	nM	CHEMBL3889586
7.08	IC50	83	nM	CHEMBL3939958
7.03	Kd	94	nM	CHEMBL3939958
7.03	Kd	94	nM	CHEMBL4449240
7.01	IC50	98	nM	CHEMBL3916023
7.01	Kd	97	nM	CHEMBL3939958
6.85	IC50	140	nM	CHEMBL3942693
6.80	IC50	160	nM	CHEMBL3934881
6.77	IC50	170	nM	CHEMBL3987134
6.72	IC50	190	nM	CHEMBL3953637
6.70	Kd	200	nM	CHEMBL3780251
6.70	IC50	200	nM	CHEMBL3969494
6.62	IC50	240	nM	CHEMBL3933207
6.54	Kd	290	nM	CHEMBL3234443
6.32	IC50	480	nM	CHEMBL3973366
6.22	Kd	600	nM	CHEMBL4635096
6.19	IC50	640	nM	CHEMBL3898460
6.16	Kd	700	nM	CHEMBL4640223
6.12	IC50	750	nM	CHEMBL3937936
6.11	IC50	770	nM	CHEMBL3925993
6.10	Kd	800	nM	CHEMBL3780712
6.10	Kd	800	nM	CHEMBL4646516
5.92	IC50	1200	nM	CHEMBL3943850
5.77	Kd	1700	nM	CHEMBL4637043
5.57	IC50	2700	nM	CHEMBL3944916
5.52	IC50	3000	nM	CHEMBL3935965
5.47	IC50	3400	nM	CHEMBL3949885
5.43	Kd	3700	nM	CHEMBL3234136
5.28	IC50	5200	nM	CHEMBL3978944
5.16	IC50	6900	nM	CHEMBL3980951
5.10	IC50	7900	nM	CHEMBL3905193
5.01	IC50	9700	nM	CHEMBL3970686

PubChem BioAssay actives

34 with measured affinity, of 69 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
methyl (2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[(4-tert-butylbenzoyl)amino]-3-phenylpropanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-6-[propan-2-yl(propyl)amino]hexanoyl]amino]-3-hydroxypropanoate	1319524: Antagonist activity at recombinant human N-terminal His-tagged CBX4 chromodomain (8 to 65 residues) expressed in Escherichia coli Rosetta BL21(DE3)pLysS using biotin-labeled H3K9me3 measured after 30 mins by AlphaScreen assay	ic50	0.0620	uM
methyl (2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[(4-tert-butylbenzoyl)amino]-3-phenylpropanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-6-[ethyl(propan-2-yl)amino]hexanoyl]amino]-3-hydroxypropanoate	1319524: Antagonist activity at recombinant human N-terminal His-tagged CBX4 chromodomain (8 to 65 residues) expressed in Escherichia coli Rosetta BL21(DE3)pLysS using biotin-labeled H3K9me3 measured after 30 mins by AlphaScreen assay	ic50	0.0750	uM
[(5S)-5-[[(2S)-2-[[(2S)-2-[[(2S)-2-[(4-tert-butylbenzoyl)amino]-3-phenylpropanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-6-[[(2S)-3-hydroxy-1-methoxy-1-oxopropan-2-yl]amino]-6-oxohexyl]-trimethylazanium	1319524: Antagonist activity at recombinant human N-terminal His-tagged CBX4 chromodomain (8 to 65 residues) expressed in Escherichia coli Rosetta BL21(DE3)pLysS using biotin-labeled H3K9me3 measured after 30 mins by AlphaScreen assay	ic50	0.0750	uM
methyl (2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[(4-tert-butylbenzoyl)amino]-3-phenylpropanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-6-(diethylamino)hexanoyl]amino]-3-hydroxypropanoate	1319524: Antagonist activity at recombinant human N-terminal His-tagged CBX4 chromodomain (8 to 65 residues) expressed in Escherichia coli Rosetta BL21(DE3)pLysS using biotin-labeled H3K9me3 measured after 30 mins by AlphaScreen assay	ic50	0.0830	uM
methyl (2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[(4-tert-butylbenzoyl)amino]propanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-6-(diethylamino)hexanoyl]amino]-3-hydroxypropanoate	1578930: Inhibition of CBX4 (unknown origin) assessed as dissociation constant by isothermal titration calorimetry	kd	0.0940	uM
methyl (2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[(4-tert-butylbenzoyl)amino]-3-[4-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]phenyl]propanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-6-(diethylamino)hexanoyl]amino]-3-hydroxypropanoate	1319524: Antagonist activity at recombinant human N-terminal His-tagged CBX4 chromodomain (8 to 65 residues) expressed in Escherichia coli Rosetta BL21(DE3)pLysS using biotin-labeled H3K9me3 measured after 30 mins by AlphaScreen assay	ic50	0.0980	uM
4-tert-butyl-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-(diethylamino)-1-[[(2S)-1-(dimethylamino)-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]benzamide	1319524: Antagonist activity at recombinant human N-terminal His-tagged CBX4 chromodomain (8 to 65 residues) expressed in Escherichia coli Rosetta BL21(DE3)pLysS using biotin-labeled H3K9me3 measured after 30 mins by AlphaScreen assay	ic50	0.1400	uM
methyl (2S)-2-[[(2S)-6-(diethylamino)-2-[[(2S)-4-methyl-2-[[(2S)-2-[[(2S)-3-phenyl-2-[(4-propan-2-ylbenzoyl)amino]propanoyl]amino]propanoyl]amino]pentanoyl]amino]hexanoyl]amino]-3-hydroxypropanoate	1319524: Antagonist activity at recombinant human N-terminal His-tagged CBX4 chromodomain (8 to 65 residues) expressed in Escherichia coli Rosetta BL21(DE3)pLysS using biotin-labeled H3K9me3 measured after 30 mins by AlphaScreen assay	ic50	0.1600	uM
methyl (2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-3-[4-(aminomethyl)phenyl]-2-[(4-tert-butylbenzoyl)amino]propanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-6-(diethylamino)hexanoyl]amino]-3-hydroxypropanoate	1319524: Antagonist activity at recombinant human N-terminal His-tagged CBX4 chromodomain (8 to 65 residues) expressed in Escherichia coli Rosetta BL21(DE3)pLysS using biotin-labeled H3K9me3 measured after 30 mins by AlphaScreen assay	ic50	0.1700	uM
methyl (2S)-2-[[(2S)-6-(diethylamino)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[(4-ethylbenzoyl)amino]-3-phenylpropanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]amino]-3-hydroxypropanoate	1319524: Antagonist activity at recombinant human N-terminal His-tagged CBX4 chromodomain (8 to 65 residues) expressed in Escherichia coli Rosetta BL21(DE3)pLysS using biotin-labeled H3K9me3 measured after 30 mins by AlphaScreen assay	ic50	0.1900	uM
[(5S)-6-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-6-[[3-carboxy-4-(3-hydroxy-6-oxoxanthen-9-yl)phenyl]carbamothioylamino]-1-oxohexan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-5-[[(2S)-2-[[(2S)-2-[[(2S)-2-[(4-bromobenzoyl)amino]-3-phenylpropanoyl]amino]propanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-6-oxohexyl]-trimethylazanium	1288272: Binding affinity to N-terminal His6-tagged human CBX4 (8 to 65 residues) expressed in Escherichia coli BL21 using FITC-peptide-3 as competitive binding probe by fluorescence polarization assay	kd	0.2000	uM
4-tert-butyl-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-(diethylamino)-1-(2-hydroxyethylamino)-1-oxohexan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]benzamide	1319524: Antagonist activity at recombinant human N-terminal His-tagged CBX4 chromodomain (8 to 65 residues) expressed in Escherichia coli Rosetta BL21(DE3)pLysS using biotin-labeled H3K9me3 measured after 30 mins by AlphaScreen assay	ic50	0.2000	uM
(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[(4-tert-butylbenzoyl)amino]-3-phenylpropanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-6-(diethylamino)hexanoyl]amino]-3-hydroxypropanoic acid	1319524: Antagonist activity at recombinant human N-terminal His-tagged CBX4 chromodomain (8 to 65 residues) expressed in Escherichia coli Rosetta BL21(DE3)pLysS using biotin-labeled H3K9me3 measured after 30 mins by AlphaScreen assay	ic50	0.2400	uM
[(5S)-5-[[(2S)-2-cyclopentyl-2-[[(2S)-2-[[(2S)-2-[(4-methoxycarbonylbenzoyl)amino]-3-phenylpropanoyl]amino]propanoyl]amino]acetyl]amino]-6-(1,3-dihydroxypropan-2-ylamino)-6-oxohexyl]-trimethylazanium	1129999: Binding affinity to CBX4 (unknown origin) by isothermal titration calorimetry assay	kd	0.2900	uM
methyl (2S)-2-[[(2S)-6-(diethylamino)-2-[[(2S)-4-methyl-2-[[(2S)-2-[[(2S)-3-phenyl-2-[[4-(trifluoromethyl)benzoyl]amino]propanoyl]amino]propanoyl]amino]pentanoyl]amino]hexanoyl]amino]-3-hydroxypropanoate	1319524: Antagonist activity at recombinant human N-terminal His-tagged CBX4 chromodomain (8 to 65 residues) expressed in Escherichia coli Rosetta BL21(DE3)pLysS using biotin-labeled H3K9me3 measured after 30 mins by AlphaScreen assay	ic50	0.4800	uM
[(5S)-6-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-6-[[3-carboxy-4-(3-hydroxy-6-oxoxanthen-9-yl)phenyl]carbamothioylamino]-1-oxohexan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-5-[[(2S)-2-[[(2S)-2-[[(2S)-2-[(4-bromobenzoyl)amino]-3-phenylpropanoyl]amino]butanoyl]amino]-2-cyclopentylacetyl]amino]-6-oxohexyl]-trimethylazanium	1650076: Binding affinity to CBX4 (unknown origin) assessed as dissociation constant by fluorescence polarization analysis	kd	0.6000	uM
methyl (2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[(4-tert-butylbenzoyl)amino]-3-phenylpropanoyl]amino]butanoyl]amino]-4-methylpentanoyl]amino]-6-(diethylamino)hexanoyl]amino]-3-hydroxypropanoate	1319524: Antagonist activity at recombinant human N-terminal His-tagged CBX4 chromodomain (8 to 65 residues) expressed in Escherichia coli Rosetta BL21(DE3)pLysS using biotin-labeled H3K9me3 measured after 30 mins by AlphaScreen assay	ic50	0.6400	uM
[(5S)-6-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-6-[[3-carboxy-4-(3-hydroxy-6-oxoxanthen-9-yl)phenyl]carbamothioylamino]-1-oxohexan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-5-[[(2S)-2-[[(2S)-2-[[(2S)-2-[(4-bromobenzoyl)amino]-3-phenylpropanoyl]amino]butanoyl]amino]-3-phenylpropanoyl]amino]-6-oxohexyl]-trimethylazanium	1650076: Binding affinity to CBX4 (unknown origin) assessed as dissociation constant by fluorescence polarization analysis	kd	0.7000	uM
methyl (2S)-2-[[(2S)-6-(diethylamino)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[(4-methoxybenzoyl)amino]-3-phenylpropanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]amino]-3-hydroxypropanoate	1319524: Antagonist activity at recombinant human N-terminal His-tagged CBX4 chromodomain (8 to 65 residues) expressed in Escherichia coli Rosetta BL21(DE3)pLysS using biotin-labeled H3K9me3 measured after 30 mins by AlphaScreen assay	ic50	0.7500	uM
methyl (2S)-2-[[(2S)-6-(diethylamino)-2-[[(2S)-4-methyl-2-[[(2S)-2-[[(2S)-2-[(4-methylbenzoyl)amino]-3-phenylpropanoyl]amino]propanoyl]amino]pentanoyl]amino]hexanoyl]amino]-3-hydroxypropanoate	1319524: Antagonist activity at recombinant human N-terminal His-tagged CBX4 chromodomain (8 to 65 residues) expressed in Escherichia coli Rosetta BL21(DE3)pLysS using biotin-labeled H3K9me3 measured after 30 mins by AlphaScreen assay	ic50	0.7700	uM
[(5S)-6-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-6-[[3-carboxy-4-(3-hydroxy-6-oxoxanthen-9-yl)phenyl]carbamothioylamino]-1-oxohexan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-5-[[(2S)-2-[[(2S)-2-[[(2S)-2-[(4-bromobenzoyl)amino]-3-phenylpropanoyl]amino]butanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-6-oxohexyl]-trimethylazanium	1288272: Binding affinity to N-terminal His6-tagged human CBX4 (8 to 65 residues) expressed in Escherichia coli BL21 using FITC-peptide-3 as competitive binding probe by fluorescence polarization assay	kd	0.8000	uM
[(5S)-6-[[(2S)-1-amino-3-hydroxy-1-oxopropan-2-yl]amino]-5-[[(2S)-2-[[(2S)-2-[[(2S)-2-[3-[[3-carboxy-4-(3-hydroxy-6-oxoxanthen-9-yl)phenyl]carbamothioylamino]propanoylamino]-3-phenylpropanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-6-oxohexyl]-trimethylazanium	1650076: Binding affinity to CBX4 (unknown origin) assessed as dissociation constant by fluorescence polarization analysis	kd	0.8000	uM
methyl 4-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-(diethylamino)-1-[[(2S)-3-hydroxy-1-methoxy-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]carbamoyl]benzoate	1319524: Antagonist activity at recombinant human N-terminal His-tagged CBX4 chromodomain (8 to 65 residues) expressed in Escherichia coli Rosetta BL21(DE3)pLysS using biotin-labeled H3K9me3 measured after 30 mins by AlphaScreen assay	ic50	1.2000	uM
[(5S)-6-[[(2S)-1-amino-3-hydroxy-1-oxopropan-2-yl]amino]-5-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[3-[[3-carboxy-4-(3-hydroxy-6-oxoxanthen-9-yl)phenyl]carbamothioylamino]propanoylamino]-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-6-oxohexyl]-trimethylazanium	1650076: Binding affinity to CBX4 (unknown origin) assessed as dissociation constant by fluorescence polarization analysis	kd	1.7000	uM
methyl (2S)-2-[[(2S)-6-(diethylamino)-2-[[(2S)-4-methyl-2-[[(2S)-2-[[(2S)-2-[(3-methylbenzoyl)amino]-3-phenylpropanoyl]amino]propanoyl]amino]pentanoyl]amino]hexanoyl]amino]-3-hydroxypropanoate	1319524: Antagonist activity at recombinant human N-terminal His-tagged CBX4 chromodomain (8 to 65 residues) expressed in Escherichia coli Rosetta BL21(DE3)pLysS using biotin-labeled H3K9me3 measured after 30 mins by AlphaScreen assay	ic50	2.7000	uM
methyl (2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-benzamido-3-phenylpropanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-6-(diethylamino)hexanoyl]amino]-3-hydroxypropanoate	1319524: Antagonist activity at recombinant human N-terminal His-tagged CBX4 chromodomain (8 to 65 residues) expressed in Escherichia coli Rosetta BL21(DE3)pLysS using biotin-labeled H3K9me3 measured after 30 mins by AlphaScreen assay	ic50	3.0000	uM
methyl (2S)-2-[[(2S)-6-(diethylamino)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-(1H-indol-3-yl)acetyl]amino]-3-phenylpropanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]amino]-3-hydroxypropanoate	1319524: Antagonist activity at recombinant human N-terminal His-tagged CBX4 chromodomain (8 to 65 residues) expressed in Escherichia coli Rosetta BL21(DE3)pLysS using biotin-labeled H3K9me3 measured after 30 mins by AlphaScreen assay	ic50	3.4000	uM
[(5S)-5-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-3-phenylpropanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-6-[[(2S)-1-amino-3-hydroxy-1-oxopropan-2-yl]amino]-6-oxohexyl]-trimethylazanium	1129999: Binding affinity to CBX4 (unknown origin) by isothermal titration calorimetry assay	kd	3.7000	uM
methyl (2S)-2-[[(2S)-6-(diethylamino)-2-[[(2S)-4-methyl-2-[[(2S)-2-[[(2S)-2-[(2-naphthalen-2-ylacetyl)amino]-3-phenylpropanoyl]amino]propanoyl]amino]pentanoyl]amino]hexanoyl]amino]-3-hydroxypropanoate	1319524: Antagonist activity at recombinant human N-terminal His-tagged CBX4 chromodomain (8 to 65 residues) expressed in Escherichia coli Rosetta BL21(DE3)pLysS using biotin-labeled H3K9me3 measured after 30 mins by AlphaScreen assay	ic50	5.2000	uM
[(5S)-5-[[(2S)-2-[[(2S)-2-[[(2S)-2-benzamido-3-phenylpropanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-6-[[(2S)-3-hydroxy-1-methoxy-1-oxopropan-2-yl]amino]-6-oxohexyl]-trimethylazanium	1319524: Antagonist activity at recombinant human N-terminal His-tagged CBX4 chromodomain (8 to 65 residues) expressed in Escherichia coli Rosetta BL21(DE3)pLysS using biotin-labeled H3K9me3 measured after 30 mins by AlphaScreen assay	ic50	6.9000	uM
methyl (2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[(4-tert-butylbenzoyl)amino]-3-phenylpropanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-6-(diethylamino)hexanoyl]amino]-3-hydroxypropanoate	1319524: Antagonist activity at recombinant human N-terminal His-tagged CBX4 chromodomain (8 to 65 residues) expressed in Escherichia coli Rosetta BL21(DE3)pLysS using biotin-labeled H3K9me3 measured after 30 mins by AlphaScreen assay	ic50	7.9000	uM
methyl (2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-(4-tert-butylphenyl)acetyl]amino]-3-phenylpropanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-6-(diethylamino)hexanoyl]amino]-3-hydroxypropanoate	1319524: Antagonist activity at recombinant human N-terminal His-tagged CBX4 chromodomain (8 to 65 residues) expressed in Escherichia coli Rosetta BL21(DE3)pLysS using biotin-labeled H3K9me3 measured after 30 mins by AlphaScreen assay	ic50	9.7000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression, increases methylation	4
Tunicamycin	increases expression	3
Cyclosporine	increases expression	3
sodium arsenite	affects cotreatment, increases abundance, increases expression	2
Acetaminophen	increases expression	2
Arsenic	affects methylation, affects cotreatment, increases abundance, increases expression	2
Cisplatin	increases expression	2
Formaldehyde	increases expression	2
Tobacco Smoke Pollution	increases expression	2
aristolochic acid I	increases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
FR900359	affects phosphorylation	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects expression	1
lead acetate	increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
diethyl maleate	increases expression	1
arsenite	increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	increases expression	1
manganese chloride	increases expression, affects cotreatment, increases abundance	1
potassium chromate(VI)	affects cotreatment, increases expression	1
epigallocatechin gallate	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
chloropicrin	increases expression	1
perfluoro-n-nonanoic acid	increases expression	1
deguelin	increases expression	1
fenpyroximate	increases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	increases expression	1

ChEMBL screening assays

11 unique, capped per target: 11 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3242418	Binding	Binding affinity to CBX4 (unknown origin) by isothermal titration calorimetry assay	Chromodomain antagonists that target the polycomb-group methyllysine reader protein chromobox homolog 7 (CBX7). — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B9VU	Abcam HEK293 CBX4 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00815633	PHASE4	TERMINATED	A Pilot Study of Alefacept for the Treatment of Pityriasis Rubra Pilaris
NCT07497620	PHASE4	NOT_YET_RECRUITING	Bimzelx (Bimekizumab) For The Treatment Of Adult Onset PRP
NCT03485976	PHASE2	COMPLETED	Ixekizumab in the Treatment of Pityriasis Rubra Pilaris (PRP)
NCT03975153	PHASE2	COMPLETED	Guselkumab in the Treatment of Pityriasis Rubra Pilaris (PRP)
NCT06444399	PHASE2	RECRUITING	Deucravacitinib (BMS-986165) for Pityriasis Rubra Pilaris
NCT03342573	PHASE1	COMPLETED	Cosentyx (Secukinumab) for the Treatment of Adult Onset Pityriasis Rubra Pilaris