CYBB

Summary

CYBB (cytochrome b-245 beta chain, HGNC:2578) is a protein-coding gene on chromosome Xp21.1-p11.4, encoding NADPH oxidase 2 (P04839). Catalytic subunit of the phagocyte NADPH oxidase complex that mediates the transfer of electrons from cytosolic NADPH to O2 to produce the superoxide anion (O2(-)). It is haploinsufficient (ClinGen: sufficient evidence).

Cytochrome b (-245) is composed of cytochrome b alpha (CYBA) and beta (CYBB) chain. It has been proposed as a primary component of the microbicidal oxidase system of phagocytes. CYBB deficiency is one of five described biochemical defects associated with chronic granulomatous disease (CGD). In this disorder, there is decreased activity of phagocyte NADPH oxidase; neutrophils are able to phagocytize bacteria but cannot kill them in the phagocytic vacuoles. The cause of the killing defect is an inability to increase the cell’s respiration and consequent failure to deliver activated oxygen into the phagocytic vacuole.

Source: NCBI Gene 1536 — RefSeq curated summary.

At a glance

• Gene–disease (curated): granulomatous disease, chronic, X-linked (Definitive, GenCC) — +2 more curated relationships
• Clinical variants (ClinVar): 919 total — 170 pathogenic, 42 likely-pathogenic
• Phenotypes (HPO): 55
• Druggable target: yes — 4 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000397

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2578
Approved symbol	CYBB
Name	cytochrome b-245 beta chain
Location	Xp21.1-p11.4
Locus type	gene with protein product
Status	Approved
Aliases	GP91-PHOX, NOX2, GP91PHOX, p91-PHOX
Ensembl gene	ENSG00000165168
Ensembl biotype	protein_coding
OMIM	300481
Entrez	1536

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 4 protein_coding, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000378588, ENST00000492288, ENST00000696170, ENST00000696171, ENST00000696172, ENST00000696173, ENST00000851337, ENST00000968558

RefSeq mRNA: 1 — MANE Select: NM_000397 NM_000397

CCDS: CCDS14242

Canonical transcript exons

ENST00000378588 — 13 exons

Exon	Start	End
ENSE00001090916	37793665	37793810
ENSE00003568515	37783490	37783600
ENSE00003589482	37791975	37792059
ENSE00003634819	37782088	37782183
ENSE00003966300	37809567	37809691
ENSE00003966301	37801256	37801348
ENSE00003966303	37798955	37799084
ENSE00003966304	37810791	37813461
ENSE00003966305	37806387	37806533
ENSE00003966308	37780059	37780122
ENSE00003966309	37805006	37805168
ENSE00003966311	37795951	37796141
ENSE00003966313	37803877	37804130

Expression profiles

Bgee: expression breadth ubiquitous, 246 present calls, max score 99.58.

FANTOM5 (CAGE): breadth broad, TPM avg 40.3810 / max 1912.4159, expressed in 476 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
195901	37.7136	476
195900	2.6330	315
195910	0.0343	17

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	99.58	gold quality
mononuclear cell	CL:0000842	99.53	gold quality
leukocyte	CL:0000738	99.48	gold quality
granulocyte	CL:0000094	98.35	gold quality
bone marrow	UBERON:0002371	98.06	gold quality
bone marrow cell	CL:0002092	97.93	gold quality
synovial joint	UBERON:0002217	96.69	gold quality
blood	UBERON:0000178	96.36	gold quality
trabecular bone tissue	UBERON:0002483	96.21	gold quality
vermiform appendix	UBERON:0001154	95.70	gold quality
lymph node	UBERON:0000029	95.27	gold quality
decidua	UBERON:0002450	94.42	gold quality
spleen	UBERON:0002106	93.65	gold quality
caecum	UBERON:0001153	91.90	gold quality
layer of synovial tissue	UBERON:0007616	91.38	gold quality
gall bladder	UBERON:0002110	91.12	gold quality
rectum	UBERON:0001052	90.90	gold quality
calcaneal tendon	UBERON:0003701	89.94	gold quality
lower lobe of lung	UBERON:0008949	89.00	gold quality
upper lobe of lung	UBERON:0008948	87.84	gold quality
lung	UBERON:0002048	87.75	gold quality
upper lobe of left lung	UBERON:0008952	87.73	gold quality
tendon	UBERON:0000043	87.68	gold quality
mucosa of sigmoid colon	UBERON:0004993	87.48	gold quality
superficial temporal artery	UBERON:0001614	86.79	gold quality
smooth muscle tissue	UBERON:0001135	86.28	gold quality
right coronary artery	UBERON:0001625	86.24	gold quality
right lung	UBERON:0002167	85.66	gold quality
placenta	UBERON:0001987	84.99	gold quality
right adrenal gland cortex	UBERON:0035827	84.82	gold quality

Single-cell (SCXA)

Detected in 22 experiment(s), a significant marker in 22.

Experiment	Marker?	Max mean expression
E-GEOD-150728	yes	2680.68
E-GEOD-130148	yes	2001.60
E-HCAD-15	yes	1863.28
E-MTAB-8498	yes	1341.21
E-MTAB-9221	yes	1060.55
E-MTAB-9067	yes	542.58
E-CURD-6	yes	351.40
E-HCAD-1	yes	84.14
E-CURD-122	yes	81.75
E-MTAB-6701	yes	64.44
E-HCAD-10	yes	55.54
E-MTAB-8410	yes	50.11
E-MTAB-6678	yes	42.55
E-GEOD-135922	yes	40.02
E-MTAB-9467	yes	35.41

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPZ, CUX1, ELF1, EP300, GATA1, GATA2, GATA3, GLI3, HIF1A, HMGA1, HOXA10, HOXA9, IRF1, IRF2, IRF8, JUN, MEIS1, NFKB, NR4A3, PBX1, RELA, SATB1, SPI1, STAT3

miRNA regulators (miRDB)

122 targeting CYBB, 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-3646	100.00	73.56	5283
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-17-5P	99.89	73.83	2665

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• novel mutations in X-linked chronic granulomatous disease (PMID:11462241)
• p22(phox), gp91(phox), p47(phox), p67(phox), and p40(phox) existed as a functional complex in the cytoskeletal fraction. (PMID:11893732)
• PU.1, HAF-1 trans activation of gp91(phox) promoter (PMID:11926990)
• analyzed DNA from two unusual X-CGD patients and established the genetic basis for their phenotype (PMID:12139950)
• In nonatherosclerotic aortic intima, gp91phox expression is restricted to 28.4+/-1.4% of intimal smooth muscle cells; in fatty streaks, macrophages and macrophage-derived foam cells express high amounts of gp91phox. (PMID:12482831)
• gp91(phox) protein with a Y41D mutation and modest superoxide activity in chronic granulomatous disease (PMID:12589359)
• histidine 115 is required for proton conduction by both full-length gp91 (phox) and the N-terminal 230-amino-acid fragment of gp91 (phox). (PMID:12768347)
• adenosine pretreatment of fMLF-stimulated neutrophils results in decreased plasma membrane/secretory granule content of the flavocytochrome b components p22phox and gp91phox of the NADPH oxidase, which correlates with inhibition of ROS production (PMID:12772776)
• promoter activity repressed by SATB1 and P300 complex; the repressed activity is partially released by CDP binding to the CCAAT element directly downstream of the AT-rich region (PMID:14605447)
• Cells expressed gp91phox homologs Nox1, Nox2, and Nox4. Keratinocytes expressed Nox distinct from phox isoform of phagocytes. Source of superoxide that may regulate cell proliferation and host defense in skin and oral mucosa. (PMID:15102091)
• DNA phasing generated by TA dinucleotide polymorphisms may influence the expression level of gp91 phox of NADPH oxidase and protect against severe falciparum malaria. (PMID:15181570)
• The N-terminus of Nox2 is present in the mature protein and is located to the cytoplasmic side of the plasma membrane. (PMID:15233623)
• Platelet CD40L expression occurs via arachidonic acid-mediated gp91phox activation. (PMID:15249506)
• NAD(P)H oxidase activity is associated with increased protein levels of p22phox, p47phox, and p67phox, and increased p22phox and nox2 (gp91phox) mRNA expression. The NAD(P)H oxidase is predominantly nox2-based in saphenous veins. (PMID:15256399)
• a woman with a novel mutation in CYBB (CCG[90-92]–>GGT), predicting Tyr30Arg31–>stop, Val in gp91phox, who presented with clinical symptoms at the age of 66 (PMID:15308575)
• significantly reduced at the Anaplasma phagocytophilum phagosome (PMID:15322037)
• The presence of outward proton currents in COS-7 cells expressing gp91phox provides further support for our proposed role for gp91phox as the NADPH oxidase-associated proton channel (PMID:15377283)
• 11 different mutations in the CYBB gene were identified, and 7 of them were novel. The types of mutations were intronic, single-nucleotide substitution resulting in nonsense or missense codons and 1 or 2 nucleotide deletions resulting in frameshifts. (PMID:15454837)
• His119, in addition to His115, is required for the conduction of protons through Nox2. (PMID:15479231)
• ANP is a novel endogenous activator of endothelial Nox/Nox2. (PMID:15569826)
• CYBB is a common target gene repressed by HoxA10 and activated by HoxA9, and Meis1 and Nup98-hoxA9 have roles in repressing myeloid-specific gene transcription (PMID:15681849)
• the alpha-helical loop of the C-terminal of Nox2 is probably involved in the correct assembly of the NADPH oxidase complex occurring during activation, permitting cytosolic factor translocation and electron transfer from NADPH to FAD (PMID:15684431)
• mRNA expression and localization of NOX2 in human umbilical vein endothelial cells. (PMID:15706079)
• monoclonal antibody CL5 was used to probe for the presence of gp91phox in membrane preparations from neutrophils of patients with nine genetically distinct forms of X-linked chronic granulomatous disease (PMID:15777347)
• NOX2 and NOX4 have roles as redox messengers in the activation of intracellular signaling pathways leading (or contributing) to mitochondriogenesis, cell survival, and differentiation in hematopoietic stem cells (PMID:15883163)
• IQGAP1 may function to link Nox2 to actin at the leading edge, thereby facilitating reactive oxygen species production at the site of injury, which may contribute to endothelial cell migration (PMID:16179592)
• These results suggest that APP-dependent microglia activation and subsequent reactive oxygen species generation by the phagocyte NADPH oxidase play a crucial role in neuronal killing in a cellular model of Alzheimer’s disease (PMID:16260066)
• Rac1 facilitated the recruitment of Nox2 into the endosomal compartment and subsequent redox-dependent recruitment of TRAF6 to the MyD88/IL-1R1 complex. (PMID:16354686)
• chronic granulomatous disease arose due to a splice-supporting mutation in the last position of a cryptic exon towards the middle of intron 6 of the CYBB (gp91-phox) gene (PMID:16516412)
• NOX2 plays a critical role in conferring DCs the ability to function as specialized phagocytes adapted to process antigens rather than kill pathogens. (PMID:16839887)
• analysis of the p22phox subunit of flavocytochrome b558: identification of regions critical for gp91phox maturation and NADPH oxidase activity (PMID:16895900)
• In endothelial cells, NOX2 and NOX4, but not NOX1, equally contributed to ROS generation and proliferation under basal conditions, indicating that a complex relation between NOX homologues controls endothelial function. (PMID:16987004)
• analysis of the integral membrane protein flavocytochrome b(558) by mass spectrometry (PMID:17015440)
• In a three-dimensional model of the C-terminal tail of Nox2, Leu505 appears to have a strategic position just at the entry of the NADPH binding site and at the end of the alpha-helical loop (residues 484-504), a potential cytosolic factor binding region. (PMID:17060362)
• De novo null mutations affecting the CYBB gene that encodes the gp91 protein were found in both cases in the heterozygous state of CGD. (PMID:17089090)
• Endothelial-targeted Nox2 overexpression is sufficient to increase vascular NADPH oxidase activity, activate downstream signaling pathways, and potentiate hemodynamic response to angiotensin II, despite increases in vascular antioxidant enzymes. (PMID:17363703)
• produce proteoliposomes containing gp91(phox) protein and demonstrate that these proteins exhibit activities similar to their cellular counterpart (PMID:17848987)
• study shows HIV-1 Tat signaling, leading to concurrent but separate Nox4-dependent Ras/ERK activation, and Nox2-dependent JNK activation; Tat signaling, therefore, provides an example of Nox-specific differential control of MAP kinase pathways (PMID:17940286)
• Src homology-containing tyrosine phosphatase 2 activation blocks IFN consensus sequence-binding protein (ICSBP) induced CYBB transcription. (PMID:18089853)
• Aged transgenic mice overexpressing the Swedish mutation of amyloid precursor protein and lacking the catalytic subunit Nox2 of NADPH oxidase do not develop oxidative stress, cerebrovascular dysfunction, or behavioral decline. (PMID:18202172)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cybb	ENSDARG00000056615
mus_musculus	Cybb	ENSMUSG00000015340
rattus_norvegicus	Cybb	ENSRNOG00000003622

Paralogs (6): NOX1 (ENSG00000007952), NOX3 (ENSG00000074771), NOX4 (ENSG00000086991), DUOX1 (ENSG00000137857), DUOX2 (ENSG00000140279), NOX5 (ENSG00000255346)

Protein

Protein identifiers

NADPH oxidase 2 — P04839 (reviewed: P04839)

Alternative names: CGD91-phox, Cytochrome b(558) subunit beta, Cytochrome b-245 heavy chain, Heme-binding membrane glycoprotein gp91phox, Neutrophil cytochrome b 91 kDa polypeptide, Superoxide-generating NADPH oxidase heavy chain subunit, gp91-1, gp91-phox, p22 phagocyte B-cytochrome

All UniProt accessions (5): A0A0S2Z3S6, A0A8Q3SIF1, A0A8Q3SIJ1, A0A8Q3WMA3, P04839

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic subunit of the phagocyte NADPH oxidase complex that mediates the transfer of electrons from cytosolic NADPH to O2 to produce the superoxide anion (O2(-)). In the activated complex, electrons are first transferred from NADPH to flavin adenine dinucleotide (FAD) and subsequently transferred via two heme molecules to molecular oxygen, producing superoxide through an outer-sphere reaction. Activation of the NADPH oxidase complex is initiated by the assembly of cytosolic subunits of the NADPH oxidase complex with the core NADPH oxidase complex to form a complex at the plasma membrane or phagosomal membrane. This activation process is initiated by phosphorylation dependent binding of the cytosolic NCF1/p47-phox subunit to the C-terminus of CYBA/p22-phox. NADPH oxidase complex assembly is impaired through interaction with NRROS.

Subunit / interactions. Component of the phagocyte NADPH oxidase core complex/cytochrome b558 complex, composed of CYBB (heavy chain (beta)) and CYBA (light chain (alpha)). Component of the phagocyte NADPH oxidase complex composed of an obligatory core heterodimer formed by the membrane proteins CYBA and CYBB and the cytosolic regulatory subunits NCF1/p47-phox, NCF2/p67-phox, NCF4/p40-phox and the small GTPase RAC1 or RAC2. Interacts with NCF1 (phosphorylated form). Interacts with NCF2; the interaction is enhanced in the presence of GBP7. Interacts with RAC2. Interacts with RAC1. Interacts with calprotectin (S100A8/9). Interacts with NRROS; the interaction is direct and impairs formation of a stable NADPH oxidase complex. Interacts with CYBC1; CYBC1 may act as a chaperone stabilizing Cytochrome b-245 heterodimer. The CYBA-CYBB complex interacts with GBP7.

Subcellular location. Cell membrane.

Tissue specificity. Detected in neutrophils (at protein level).

Post-translational modifications. Glycosylated. Phosphorylated on Ser and Thr residues by PKC during neutrophils activation. Phosphorylation enhances the NADPH oxidase activity and stimulates its interaction with RAC2, NCF2/p67-phox, and NCF1/p47-phox. Undergoes ‘Lys-48’-linked polyubiquitination, likely by RNF145, triggering endoplasmic reticulum-associated degradation.

Disease relevance. Granulomatous disease, chronic, X-linked (CGDX) [MIM:306400] A form of chronic granulomatous disease, a primary immunodeficiency characterized by severe recurrent bacterial and fungal infections, along with manifestations of chronic granulomatous inflammation. It results from an impaired ability of phagocytes to mount a burst of reactive oxygen species in response to pathogens. The disease is caused by variants affecting the gene represented in this entry. Immunodeficiency 34 (IMD34) [MIM:300645] A form of Mendelian susceptibility to mycobacterial disease, a rare condition characterized by predisposition to illness caused by moderately virulent mycobacterial species, such as Bacillus Calmette-Guerin (BCG) vaccine, environmental non-tuberculous mycobacteria, and by the more virulent Mycobacterium tuberculosis. Other microorganisms rarely cause severe clinical disease in individuals with susceptibility to mycobacterial infections, with the exception of Salmonella which infects less than 50% of these individuals. Disease susceptibility is associated with variants affecting the gene represented in this entry.

RefSeq proteins (1): NP_000388* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000778	Cyt_b245_heavy_chain	Family
IPR013112	FAD-bd_8	Domain
IPR013121	Fe_red_NAD-bd_6	Domain
IPR013130	Fe3_Rdtase_TM_dom	Domain
IPR017927	FAD-bd_FR_type	Domain
IPR017938	Riboflavin_synthase-like_b-brl	Homologous_superfamily
IPR039261	FNR_nucleotide-bd	Homologous_superfamily
IPR050369	RBOH/FRE	Family

Pfam: PF01794, PF08022, PF08030

Catalyzed reactions (Rhea), 1 shown:

• NADPH + 2 O2 = 2 superoxide + NADP(+) + H(+) (RHEA:63180)

UniProt features (179 total): sequence variant 72, helix 27, binding site 24, strand 17, cross-link 10, topological domain 7, transmembrane region 6, turn 6, glycosylation site 3, mutagenesis site 2, domain 2, initiator methionine 1, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
3A1F	X-RAY DIFFRACTION	2
8WEJ	ELECTRON MICROSCOPY	2.79
8X2L	ELECTRON MICROSCOPY	2.99
7U8G	ELECTRON MICROSCOPY	3.2
8GZ3	ELECTRON MICROSCOPY	3.3
8KEI	ELECTRON MICROSCOPY	3.56

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P04839-F1	90.29	0.70

Antibody-complex structures (SAbDab): 5 — 7U8G, 8GZ3, 8KEI, 8WEJ, 8X2L

Functional residue map

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

Ligand- & substrate-binding residues (24): 101 (axial binding residue); 115 (axial binding residue); 199; 200; 206; 209 (axial binding residue); 222 (axial binding residue); 226; 227; 268; 280; 287 …

Post-translational modifications (10): 161, 255, 294, 299, 306, 328, 334, 381, 506, 567

Glycosylation sites (3): 132, 149, 240

Mutagenesis-validated functional residues (2):

Position	Phenotype
570	moderately decreases superoxide-generating nadph oxidase activity.

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-1222556	ROS and RNS production in phagocytes
R-HSA-1236973	Cross-presentation of particulate exogenous antigens (phagosomes)
R-HSA-3299685	Detoxification of Reactive Oxygen Species
R-HSA-4420097	VEGFA-VEGFR2 Pathway
R-HSA-5668599	RHO GTPases Activate NADPH Oxidases
R-HSA-6798695	Neutrophil degranulation
R-HSA-9013149	RAC1 GTPase cycle
R-HSA-9013404	RAC2 GTPase cycle
R-HSA-9013423	RAC3 GTPase cycle

MSigDB gene sets: 610 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_RESPONSE_TO_ETHANOL, REACTOME_INNATE_IMMUNE_SYSTEM, MCLACHLAN_DENTAL_CARIES_UP, MODULE_169, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_ACID_CHEMICAL, GOBP_INFLAMMATORY_RESPONSE, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, GOCC_SECRETORY_GRANULE, GOBP_RESPONSE_TO_CORTICOSTEROID, MODULE_45, GOBP_CELLULAR_RESPONSE_TO_CADMIUM_ION, GOBP_RESPONSE_TO_ANGIOTENSIN, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT

GO Biological Process (21): superoxide metabolic process (GO:0006801), defense response (GO:0006952), inflammatory response (GO:0006954), response to nutrient (GO:0007584), response to xenobiotic stimulus (GO:0009410), positive regulation of tumor necrosis factor production (GO:0032760), monoatomic ion transmembrane transport (GO:0034220), superoxide anion generation (GO:0042554), innate immune response (GO:0045087), respiratory burst (GO:0045730), positive regulation of angiogenesis (GO:0045766), hydrogen peroxide biosynthetic process (GO:0050665), cellular response to cadmium ion (GO:0071276), cellular response to ethanol (GO:0071361), hypoxia-inducible factor-1alpha signaling pathway (GO:0097411), response to aldosterone (GO:1904044), cellular response to L-glutamine (GO:1904845), response to angiotensin (GO:1990776), monoatomic ion transport (GO:0006811), response to ethanol (GO:0045471), cellular response to hypoxia (GO:0071456)

GO Molecular Function (13): NAD(P)H oxidase H2O2-forming activity (GO:0016174), superoxide-generating NAD(P)H oxidase activity (GO:0016175), heme binding (GO:0020037), metal ion binding (GO:0046872), protein heterodimerization activity (GO:0046982), flavin adenine dinucleotide binding (GO:0050660), NADPH binding (GO:0070402), FAD binding (GO:0071949), superoxide-generating NADPH oxidase activity (GO:0106292), protein binding (GO:0005515), electron transfer activity (GO:0009055), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on NAD(P)H, oxygen as acceptor (GO:0050664)

GO Cellular Component (14): nuclear envelope (GO:0005635), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), dendrite (GO:0030425), phagocytic vesicle membrane (GO:0030670), monoatomic ion channel complex (GO:0034702), specific granule membrane (GO:0035579), NADPH oxidase complex (GO:0043020), neuronal cell body (GO:0043025), tertiary granule membrane (GO:0070821), perinuclear endoplasmic reticulum (GO:0097038), cytoplasm (GO:0005737), membrane (GO:0016020), phagocytic vesicle (GO:0045335)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
RHO GTPase cycle	3
Innate Immune System	2
Antigen processing-Cross presentation	1
Cellular response to chemical stress	1
Signaling by VEGF	1
RHO GTPase Effectors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
response to chemical	2
response to alcohol	2
oxidoreductase activity, acting on NAD(P)H, oxygen as acceptor	2
anion binding	2
secretory granule membrane	2
reactive oxygen species metabolic process	1
response to stress	1
defense response	1
response to nutrient levels	1
tumor necrosis factor production	1
regulation of tumor necrosis factor production	1
positive regulation of tumor necrosis factor superfamily cytokine production	1
monoatomic ion transport	1
transmembrane transport	1
superoxide metabolic process	1
immune response	1
defense response to symbiont	1
metabolic process	1
angiogenesis	1
regulation of angiogenesis	1
positive regulation of vasculature development	1
hydrogen peroxide metabolic process	1
reactive oxygen species biosynthetic process	1
response to cadmium ion	1
cellular response to metal ion	1
response to ethanol	1
cellular response to alcohol	1
intracellular signal transduction	1
cellular response to hypoxia	1
response to mineralocorticoid	1
response to ketone	1
cellular response to amino acid stimulus	1
cellular response to nitrogen compound	1
cellular response to oxygen-containing compound	1
response to L-glutamine	1
response to peptide hormone	1
transport	1
tetrapyrrole binding	1
cation binding	1

Protein interactions and networks

STRING

4072 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CYBB	CYBA	P13498	999
CYBB	NCF1	P14598	999
CYBB	NCF2	P19878	999
CYBB	NCF4	Q15080	999
CYBB	RAC2	P15153	997
CYBB	AKT1	P31749	994
CYBB	NOX5	Q96PH1	987
CYBB	NOX4	Q9NPH5	984
CYBB	NOX1	Q9Y5S8	983
CYBB	NOXO1	Q8NFA2	983
CYBB	NOX3	Q9HBY0	982
CYBB	NOXA1	Q86UR1	977
CYBB	DUOX1	Q9NRD9	972
CYBB	RAP1A	P10113	969
CYBB	TLR4	O00206	872

IntAct

23 interactions, top by confidence:

A	B	Type	Score
CYBB	CYBC1	psi-mi:“MI:0915”(physical association)	0.560
TNFRSF1A	CYBB	psi-mi:“MI:0914”(association)	0.350
CD177	MYO1G	psi-mi:“MI:0914”(association)	0.350
GNG8	POTEF	psi-mi:“MI:0914”(association)	0.350
CYBB	CYBA	psi-mi:“MI:0914”(association)	0.350
KLK10	IGLL5	psi-mi:“MI:0914”(association)	0.350
RAC2	CYBB	psi-mi:“MI:0403”(colocalization)	0.270
AKT1	CYBB	psi-mi:“MI:2364”(proximity)	0.270
FBXW7	CYBB	psi-mi:“MI:2364”(proximity)	0.270
SMAD4	CYBB	psi-mi:“MI:2364”(proximity)	0.270
SPOP	CYBB	psi-mi:“MI:2364”(proximity)	0.270
CYBB	SPOP	psi-mi:“MI:2364”(proximity)	0.270
CYBB	TP53	psi-mi:“MI:2364”(proximity)	0.270
CYBB	PTEN	psi-mi:“MI:2364”(proximity)	0.270
EGFR	CYBB	psi-mi:“MI:2364”(proximity)	0.270
CYBB	BRAF	psi-mi:“MI:2364”(proximity)	0.270
CYBB	CYBC1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (22): CYBB (Synthetic Lethality), CYBB (Affinity Capture-Western), APPBP2 (Affinity Capture-Western), CYBB (Affinity Capture-Western), NCF2 (Reconstituted Complex), C17orf62 (Two-hybrid), CYBB (Affinity Capture-MS), USP34 (Affinity Capture-MS), SLC30A1 (Affinity Capture-MS), ARL10 (Affinity Capture-MS), CYBA (Affinity Capture-MS), CCDC168 (Affinity Capture-MS), CYBB (Affinity Capture-MS), CYBB (Co-localization), CYBA (Affinity Capture-Western)

ESM2 similar proteins: A3KMY4, A5D7H3, A5PF08, A5PMW0, B0JZD0, B0S5A7, B4F795, B5TYT3, B5X3W7, F1S584, O54902, P04839, P49282, P52649, P58421, Q3MHV9, Q53GD3, Q5R419, Q5R5L9, Q5XEZ5, Q66IV3, Q68EQ9, Q6AY92, Q6DHB5, Q6DHU1, Q6GN42, Q6INE8, Q6IP59, Q6IR74, Q6MG71, Q6X893, Q7SYC9, Q7T2B0, Q7TNK0, Q810F1, Q8BY89, Q8IWA5, Q8NCS7, Q8VII6, Q8VZM5

Diamond homologs: O46522, O48538, O81210, O81211, P04839, P52649, Q2HXK9, Q2HXL0, Q5R5C5, Q5ZAJ0, Q61093, Q672J9, Q672K1, Q6J2K5, Q86GL4, Q8CIZ9, Q924V1, Q948T9, Q95L74, Q9FIJ0, Q9HBY0, Q9JHI8, Q9NPH5, Q9SBI0, Q9SW17, Q9WV87, Q9XYS3, Q9Y5S8, O81209, Q3KTM0, Q8CIY2, Q8HZK2, Q8HZK3, Q8RWS6, Q8VY13, Q8W110, Q948U0, Q9ES45, Q9FJD6, Q9FLW2

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
IRF8	“up-regulates quantity by expression”	CYBB	“transcriptional regulation”
GATA1	“up-regulates quantity”	CYBB	“transcriptional regulation”
GATA2	“down-regulates quantity”	CYBB	“transcriptional regulation”
CYBB	up-regulates	ROS
CYBB	“up-regulates quantity”	superoxide	“chemical modification”
CYBB	“form complex”	“Phagocyte NADPH oxidase complex”	binding
hsa-mir-106b-5p	“down-regulates quantity by repression”	CYBB	“post transcriptional regulation”
hsa-mir-148b-3p	“down-regulates quantity by repression”	CYBB	“post transcriptional regulation”
hsa-mir-204-5p	“down-regulates quantity by repression”	CYBB	“post transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	170
Likely pathogenic	42
Uncertain significance	190
Likely benign	306
Benign	61

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1012317	NM_000397.4(CYBB):c.752G>A (p.Trp251Ter)	Pathogenic
1012321	NM_000397.4(CYBB):c.190T>C (p.Cys64Arg)	Pathogenic
1012323	NM_000397.4(CYBB):c.1271G>A (p.Trp424Ter)	Pathogenic
1048546	NM_000397.4(CYBB):c.-65C>G	Pathogenic
1068155	NM_000397.4(CYBB):c.1673del (p.Pro558fs)	Pathogenic
1070320	NM_000397.4(CYBB):c.483+1G>A	Pathogenic
1070694	NM_000397.4(CYBB):c.565del (p.Ile189fs)	Pathogenic
1071577	NM_000397.4(CYBB):c.675-2A>G	Pathogenic
1071578	NM_000397.4(CYBB):c.1151+1G>A	Pathogenic
1072432	NM_000397.4(CYBB):c.1314+1G>A	Pathogenic
1074313	NM_000397.4(CYBB):c.1519C>T (p.Gln507Ter)	Pathogenic
1074314	NM_000397.4(CYBB):c.1645C>T (p.Gln549Ter)	Pathogenic
1074351	NM_000397.4(CYBB):c.46-2A>T	Pathogenic
1076169	NM_000397.4(CYBB):c.603C>G (p.Tyr201Ter)	Pathogenic
1076290	NM_000397.4(CYBB):c.3G>A (p.Met1Ile)	Pathogenic
10920	NM_000397.4(CYBB):c.1244C>A (p.Pro415His)	Pathogenic
10921	NM_000397.4(CYBB):c.1166G>C (p.Gly389Ala)	Pathogenic
10923	NM_000397.4(CYBB):c.217C>T (p.Arg73Ter)	Pathogenic
10924	NM_000397.4(CYBB):c.731G>C (p.Cys244Ser)	Pathogenic
10925	NM_000397.4(CYBB):c.466G>A (p.Ala156Thr)	Pathogenic
10926	NM_000397.4(CYBB):c.302A>G (p.His101Arg)	Pathogenic
10927	NM_000397.4(CYBB):c.911C>G (p.Pro304Arg)	Pathogenic
10928	NM_000397.4(CYBB):c.1462-2A>G	Pathogenic
10929	NM_000397.4(CYBB):c.676C>T (p.Arg226Ter)	Pathogenic
10930	NM_000397.4(CYBB):c.252+5G>A	Pathogenic
10931	NM_000397.4(CYBB):c.1499A>G (p.Asp500Gly)	Pathogenic
10933	NM_000397.4(CYBB):c.252G>A (p.Ala84=)	Pathogenic
10934	NM_000397.4:c.484-262_484-261insLINE1	Pathogenic
10936	NM_000397.4(CYBB):c.907C>A (p.His303Asn)	Pathogenic
10937	NM_000397.4(CYBB):c.483+979G>T	Pathogenic

SpliceAI

1839 predictions. Top by Δscore:

Variant	Effect	Δscore
X:37780121:TT:T	donor_gain	1.0000
X:37780123:G:GG	donor_gain	1.0000
X:37791966:A:AG	acceptor_gain	1.0000
X:37791967:A:G	acceptor_gain	1.0000
X:37791971:A:AG	acceptor_gain	1.0000
X:37791971:AAAGT:A	acceptor_gain	1.0000
X:37791972:A:G	acceptor_gain	1.0000
X:37791973:A:AG	acceptor_gain	1.0000
X:37791974:G:GG	acceptor_gain	1.0000
X:37791974:GT:G	acceptor_gain	1.0000
X:37791974:GTGCT:G	acceptor_gain	1.0000
X:37792056:TCTGG:T	donor_loss	1.0000
X:37792057:CTGG:C	donor_loss	1.0000
X:37792058:TGGTA:T	donor_loss	1.0000
X:37792060:G:GG	donor_gain	1.0000
X:37792060:GTAA:G	donor_loss	1.0000
X:37792061:T:A	donor_loss	1.0000
X:37801008:A:T	donor_gain	1.0000
X:37804021:G:GT	donor_gain	1.0000
X:37804126:CCTAA:C	donor_gain	1.0000
X:37804128:TAA:T	donor_gain	1.0000
X:37804128:TAAG:T	donor_loss	1.0000
X:37804129:AA:A	donor_gain	1.0000
X:37804130:AG:A	donor_loss	1.0000
X:37804131:G:GG	donor_gain	1.0000
X:37804131:G:T	donor_loss	1.0000
X:37804132:T:A	donor_loss	1.0000
X:37804133:GAG:G	donor_loss	1.0000
X:37806379:A:AG	acceptor_gain	1.0000
X:37806380:T:G	acceptor_gain	1.0000

AlphaMissense

3761 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:37783537:C:A	N63K	1.000
X:37783537:C:G	N63K	1.000
X:37783587:G:C	R80T	1.000
X:37783587:G:T	R80M	1.000
X:37792023:C:G	H101D	1.000
X:37796080:T:C	F205L	1.000
X:37796082:T:A	F205L	1.000
X:37796082:T:G	F205L	1.000
X:37803944:G:A	G322E	1.000
X:37803988:T:A	W337R	1.000
X:37803988:T:C	W337R	1.000
X:37803991:C:G	H338D	1.000
X:37804054:G:T	G359W	1.000
X:37804055:G:A	G359E	1.000
X:37804055:G:T	G359V	1.000
X:37804060:T:A	W361R	1.000
X:37804060:T:C	W361R	1.000
X:37805019:G:A	G389R	1.000
X:37805019:G:C	G389R	1.000
X:37805019:G:T	G389W	1.000
X:37805020:G:A	G389E	1.000
X:37805029:G:A	G392D	1.000
X:37805077:G:A	G408E	1.000
X:37805082:G:T	G410W	1.000
X:37805083:G:A	G410E	1.000
X:37805088:G:A	G412R	1.000
X:37805088:G:C	G412R	1.000
X:37805088:G:T	G412W	1.000
X:37805089:G:A	G412E	1.000
X:37805113:T:C	L420P	1.000

dbSNP variants (sampled 300 via entrez): RS1000313472 (X:37780580 T>C), RS1000449858 (X:37810881 G>A,C), RS1000465301 (X:37790283 A>T), RS1000525992 (X:37810420 C>T), RS1000662386 (X:37781016 A>G), RS1001039667 (X:37799997 A>G), RS1001124584 (X:37805867 C>T), RS1001932011 (X:37778546 T>A), RS1002083768 (X:37788778 T>C), RS1002137446 (X:37788458 A>C,G), RS1002198776 (X:37807800 G>A), RS1002309923 (X:37798080 A>G), RS1002387333 (X:37778118 G>T), RS1002642123 (X:37794318 T>A,C,G), RS1002692986 (X:37793847 G>T)

Disease associations

OMIM: gene MIM:300481 | disease phenotypes: MIM:138990, MIM:306400, MIM:244400, MIM:300645, MIM:311250

GenCC curated gene-disease

Disease	Classification	Inheritance
granulomatous disease, chronic, X-linked	Definitive	X-linked
X-linked Mendelian susceptibility to mycobacterial diseases due to CYBB deficiency	Supportive	X-linked
chronic granulomatous disease	Supportive	Autosomal recessive

Mondo (5): granulomatous disease, chronic, X-linked (MONDO:0010600), chronic granulomatous disease (MONDO:0018305), primary ciliary dyskinesia (MONDO:0016575), X-linked Mendelian susceptibility to mycobacterial diseases due to CYBB deficiency (MONDO:0010389), ornithine carbamoyltransferase deficiency (MONDO:0010703)

Orphanet (5): Chronic granulomatous disease (Orphanet:379), Primary ciliary dyskinesia (Orphanet:244), X-linked mendelian susceptibility to mycobacterial diseases (Orphanet:319605), Ornithine transcarbamylase deficiency (Orphanet:664), OBSOLETE: X-linked mendelian susceptibility to mycobacterial diseases due to CYBB deficiency (Orphanet:319623)

HPO phenotypes

55 total (30 of 55 shown, HPO-id order):

HPO	Term
HP:0000230	Gingivitis
HP:0000246	Sinusitis
HP:0000388	Otitis media
HP:0000964	Eczematoid dermatitis
HP:0000992	Cutaneous photosensitivity
HP:0001034	Hypermelanotic macule
HP:0001287	Meningitis
HP:0001419	X-linked recessive inheritance
HP:0001541	Ascites
HP:0001744	Splenomegaly
HP:0001874	Abnormality of neutrophils
HP:0001945	Fever
HP:0002021	Pyloric stenosis
HP:0002024	Malabsorption
HP:0002202	Pleural effusion
HP:0002205	Recurrent respiratory infections
HP:0002240	Hepatomegaly
HP:0002575	Tracheoesophageal fistula
HP:0002716	Lymphadenopathy
HP:0002721	Immunodeficiency
HP:0002723	Absence of bactericidal oxidative respiratory burst in phagocytes
HP:0002724	Recurrent Aspergillus infections
HP:0002726	Recurrent Staphylococcus aureus infections
HP:0002740	Recurrent E. coli infections
HP:0002741	Recurrent Serratia marcescens infections
HP:0002742	Recurrent Klebsiella infections
HP:0002754	Osteomyelitis
HP:0002840	Lymphadenitis
HP:0002842	Recurrent Burkholderia cepacia infections
HP:0002955	Granulomatosis

GWAS associations

0 associations (top):

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D002925	Ciliary Motility Disorders	C08.200; C09.150; C16.131.077.245.500; C16.320.184.500
D006105	Granulomatous Disease, Chronic	C15.378.553.774.535; C16.320.322.233; C20.673.774.535; C23.550.291.500.423
D007619	Kartagener Syndrome	C08.127.384.500; C08.200.531; C08.695.501; C09.150.531; C14.240.400.280.500; C14.280.400.280.500; C16.131.077.245.500.531; C16.131.240.400.280.500; C16.131.740.501; C16.131.810.250.500; C16.320.184.500.531; C16.320.480
D020163	Ornithine Carbamoyltransferase Deficiency Disease	C10.228.140.163.100.937.750; C16.320.322.828; C16.320.565.100.940.750; C16.320.565.189.937.750; C18.452.132.100.937.500; C18.452.648.100.940.500; C18.452.648.189.937.500
C567068	Atypical Mycobacteriosis, Familial, X-Linked 2 (supp.)
C564210	Granulomatous Disease, Chronic, Autosomal Dominant Type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1287627 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

4 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 52,883 (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
CHEMBL80	NALOXONE	4	38,742
CHEMBL51085	EBSELEN	3	13,237
CHEMBL4303187	SETANAXIB	2	811
CHEMBL4650894	ISUZINAXIB	2	93

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — NADPH oxidases

Most potent curated ligand interactions (4 total), top 4:

Ligand	Action	Affinity	Parameter
NSC 780521	Inhibition	5.98	pIC50
compound 7c [PMID: 22041175]	Inhibition	5.87	pKi
GKT136901	Inhibition	5.82	pKi
setanaxib	Inhibition	5.76	pKi

Binding affinities (BindingDB)

49 measured of 53 human assays (53 total across all organisms); most potent 49 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
SMR000033635	KI	300 nM
2-N-(3,4-dimethylphenyl)-6-[[4-(3-methoxyphenyl)piperazin-1-yl]methyl]-1,3,5-triazine-2,4-diamine	IC50	1680 nM	US-10173988: N2-(3,4-dimethylphenyl)-6-((4-(p-tolyl)piperazin-1-yl)methyl)-1,3,5-triazine-2,4-diamine
cid_7082	IC50	9000 nM
CHEMBL3347543	IC50	12000 nM
6-[[4-(4-chlorophenyl)piperazin-1-yl]methyl]-2-N-(3,4-dimethylphenyl)-1,3,5-triazine-2,4-diamine	IC50	15000 nM	US-10173988: N2-(3,4-dimethylphenyl)-6-((4-(p-tolyl)piperazin-1-yl)methyl)-1,3,5-triazine-2,4-diamine
2-N-(3,4-dimethylphenyl)-6-[[4-(4-methylphenyl)piperazin-1-yl]methyl]-1,3,5-triazine-2,4-diamine	IC50	16000 nM	US-10173988: N2-(3,4-dimethylphenyl)-6-((4-(p-tolyl)piperazin-1-yl)methyl)-1,3,5-triazine-2,4-diamine
2-N-(3-chloro-4-methylphenyl)-6-[[4-(3-methoxyphenyl)piperazin-1-yl]methyl]-1,3,5-triazine-2,4-diamine	IC50	17000 nM	US-10173988: N2-(3,4-dimethylphenyl)-6-((4-(p-tolyl)piperazin-1-yl)methyl)-1,3,5-triazine-2,4-diamine
CHEMBL3347503	IC50	30000 nM
2-N-(3,4-dimethylphenyl)-6-[[4-(3-methylphenyl)piperazin-1-yl]methyl]-1,3,5-triazine-2,4-diamine	IC50	59000 nM	US-10173988: N2-(3,4-dimethylphenyl)-6-((4-(p-tolyl)piperazin-1-yl)methyl)-1,3,5-triazine-2,4-diamine
CHEMBL3347542	IC50	88000 nM
2-(4-acetylanilino)-1-[4-(4-hydroxyphenyl)piperazin-1-yl]ethanone	IC50	1e+08 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
2-(4-acetylanilino)-1-[4-(4-aminophenyl)piperazin-1-yl]ethanone	IC50	2e+08 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
methyl 2-[4-(4-methoxyphenyl)piperazine-1-carbonyl]-1H-indole-5-carboxylate	IC50	3e+08 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
2-(4-acetylanilino)-1-[4-(4-methoxyphenyl)piperazin-1-yl]ethanone	IC50	4e+08 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
1-[2-[4-(4-methoxyphenyl)piperazine-1-carbonyl]-1H-indol-5-yl]ethanone	IC50	4e+08 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
2-(4-acetylanilino)-1-[4-(4-ethoxyphenyl)piperazin-1-yl]ethanone	IC50	5e+08 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
2-(4-acetylanilino)-1-[4-(2-hydroxyphenyl)piperazin-1-yl]ethanone	IC50	5e+08 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
(5-methoxy-1H-indol-2-yl)-[4-(4-methoxyphenyl)piperazin-1-yl]methanone	IC50	5e+08 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
(5-hydroxy-1H-indol-2-yl)-[4-(4-methoxyphenyl)piperazin-1-yl]methanone	IC50	5e+08 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
1H-indol-2-yl-[4-(4-methoxyphenyl)piperazin-1-yl]methanone	IC50	5e+08 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
2-[4-(4-methoxyphenyl)piperazine-1-carbonyl]-N-methyl-1H-indole-5-carboxamide	IC50	5e+08 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
2-[4-(4-methoxyphenyl)piperazine-1-carbonyl]-1H-indole-5-carboxylic acid	IC50	5e+08 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
2-(4-acetylanilino)-1-[4-(4-methoxyphenyl)-3-methylpiperazin-1-yl]ethanone	IC50	6e+08 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
2-(3,4-difluoroanilino)-1-[4-(4-methoxyphenyl)piperazin-1-yl]ethanone	IC50	6e+08 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
(6-fluoro-1H-benzimidazol-2-yl)-[4-(4-methoxyphenyl)piperazin-1-yl]methanone	IC50	7e+08 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
(5-fluoro-3-methyl-1H-indol-2-yl)-[4-(4-methoxyphenyl)piperazin-1-yl]methanone	IC50	7e+08 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
2-[4-(4-methoxyphenyl)piperazine-1-carbonyl]-1H-indole-5-carboxamide	IC50	7e+08 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
1-[4-(4-methoxyphenyl)piperazin-1-yl]-2-(4-propan-2-ylanilino)ethanone	IC50	8e+08 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
(5,6-dimethoxy-1H-indol-2-yl)-[4-(4-methoxyphenyl)piperazin-1-yl]methanone	IC50	8e+08 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
1-[2-[4-(4-ethoxyphenyl)piperazine-1-carbonyl]-1H-indol-5-yl]ethanone	IC50	8e+08 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
[4-(4-ethoxyphenyl)piperazin-1-yl]-(6-fluoro-1H-benzimidazol-2-yl)methanone	IC50	8e+08 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
2-(3-fluoroanilino)-1-[4-(4-methoxyphenyl)piperazin-1-yl]ethanone	IC50	1e+09 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
1-[4-(4-methoxyphenyl)piperazin-1-yl]-2-(N-[2-[4-(4-methoxyphenyl)piperazin-1-yl]-2-oxoethyl]-4-propan-2-ylanilino)ethanone	IC50	1e+09 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
1-[2-[4-(4-methoxyphenyl)piperazine-1-carbonyl]-3-methyl-1H-indol-5-yl]ethanone	IC50	1e+09 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
(6-methoxy-1H-benzimidazol-2-yl)-[4-(4-methoxyphenyl)piperazin-1-yl]methanone	IC50	1e+09 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
methyl 1-(5-fluoro-1H-indole-2-carbonyl)-4-(4-methoxyphenyl)piperazine-2-carboxylate	IC50	1e+09 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
7-acetyl-3-[4-(4-methoxyphenyl)piperazine-1-carbonyl]-1H-quinolin-4-one	IC50	1e+09 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
1-[2-[4-(4-propan-2-yloxyphenyl)piperazine-1-carbonyl]-1H-indol-5-yl]ethanone	IC50	1e+09 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
2-[4-(4-propan-2-yloxyphenyl)piperazine-1-carbonyl]-3H-benzimidazole-5-carboxamide	IC50	1e+09 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
2-(4-acetylanilino)-1-[4-(3,4-dimethoxyphenyl)piperazin-1-yl]ethanone	IC50	1.3e+09 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
6-fluoro-3-[4-(4-methoxyphenyl)piperazine-1-carbonyl]-1H-quinolin-4-one	IC50	1.5e+09 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
(5-hydroxy-1H-indol-2-yl)-[4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl]methanone	IC50	1.5e+09 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
2-[4-(3-fluoro-4-methoxyphenyl)piperazine-1-carbonyl]-1H-indole-5-carboxamide	IC50	2e+09 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
2-(4-fluoroanilino)-1-[4-(4-methoxyphenyl)piperazin-1-yl]ethanone	IC50	3e+09 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
1-[2-[4-(3-fluoro-4-methoxyphenyl)piperazine-1-carbonyl]-1H-indol-5-yl]ethanone	IC50	3e+09 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
2-(4-acetylanilino)-1-[4-(2-aminophenyl)piperazin-1-yl]ethanone	IC50	4e+09 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
2-(2-fluoroanilino)-1-[4-(4-methoxyphenyl)piperazin-1-yl]ethanone	IC50	4.5e+09 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
(5-fluoro-1H-indol-2-yl)-[4-(4-methoxyphenyl)piperazin-1-yl]methanone	IC50	5e+09 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto
2-[4-(3-fluoro-4-methoxyphenyl)piperazine-1-carbonyl]-N-methyl-1H-indole-5-carboxamide	IC50	1e+10 nM	US-9428478: Piperazine derivatives, compositions, and uses related thereto

ChEMBL bioactivities

95 potent at pChembl≥5 of 155 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.52	IC50	30	nM	CHEMBL3347551
7.52	IC50	30	nM	CHEMBL3347550
7.52	IC50	30	nM	CHEMBL3733336
7.49	IC50	32.4	nM	CHEMBL3347550
7.27	Ki	54	nM	CHEMBL5413611
7.00	IC50	100	nM	DIPHENYLENEIODONIUM CHLORIDE
7.00	IC50	100	nM	CHEMBL4210329
6.87	IC50	135	nM	CHEMBL6148605
6.83	IC50	149	nM	CHEMBL5413611
6.81	IC50	155	nM	CHEMBL6148605
6.52	IC50	300	nM	EBSELEN
6.52	IC50	304	nM	CHEMBL4210329
6.44	Ki	365	nM	CHEMBL1927146
6.36	Ki	433	nM	CHEMBL1927160
6.31	IC50	490	nM	CHEMBL5426199
6.30	IC50	500	nM	CHEMBL5275943
6.30	EC50	500	nM	EBSELEN
6.29	Ki	510	nM	CHEMBL1927158
6.28	IC50	520	nM	CHEMBL5279528
6.25	IC50	567	nM	CHEMBL6148605
6.24	Ki	570	nM	ISUZINAXIB
6.23	IC50	590	nM	CELASTROL
6.19	Ki	645	nM	CHEMBL1927148
6.13	IC50	740	nM	CHEMBL5436229
6.11	Ki	780	nM	CHEMBL1927154
6.09	Ki	820	nM	CHEMBL1927159
6.04	IC50	910	nM	CHEMBL5285816
6.00	IC50	990	nM	CHEMBL5279646
6.00	IC50	1000	nM	CHEMBL5416189
5.99	Ki	1020	nM	CHEMBL1927155
5.96	IC50	1100	nM	CHEMBL5419067
5.96	IC50	1100	nM	CHEMBL4210329
5.94	Ki	1160	nM	CHEMBL1927149
5.94	Ki	1150	nM	CHEMBL1927150
5.94	Ki	1140	nM	CHEMBL1927157
5.92	IC50	1200	nM	CHEMBL5427803
5.92	Ki	1195	nM	CHEMBL1927153
5.90	IC50	1250	nM	CHEMBL5220686
5.90	Ki	1260	nM	CHEMBL1927151
5.89	Ki	1280	nM	CHEMBL1927145
5.88	IC50	1310	nM	CHEMBL5282245
5.87	Ki	1340	nM	CHEMBL1927147
5.86	Ki	1370	nM	CHEMBL1927156
5.83	IC50	1470	nM	CHEMBL5278688
5.82	Ki	1530	nM	CHEMBL1276946
5.80	IC50	1580	nM	CHEMBL5269753
5.80	IC50	1600	nM	CHEMBL5410678
5.78	IC50	1660	nM	CHEMBL5269857
5.78	IC50	1680	nM	CHEMBL5220686
5.76	Ki	1750	nM	SETANAXIB

PubChem BioAssay actives

72 with measured affinity, of 152 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(1R,8S,10S)-3-bromo-11,11-dimethyl-10-(2-methylprop-2-enyl)-9-pentyl-9-azatricyclo[6.2.2.02,7]dodeca-2(7),3,5-triene	1160720: Inhibition of full length human NOX2 transfected in COS 22 cells assessed as inhibition of lithium dodecyl sulphate-stimulated ROS generation preincubated for 15 mins followed by lithium dodecyl sulphate challenge by cell-free assay in presence of NADPH	ic50	0.0300	uM
(1R,8S,10S)-3-bromo-11,11-dimethyl-10-(2-methylprop-2-enyl)-9-(thiophen-2-ylmethyl)-9-azatricyclo[6.2.2.02,7]dodeca-2(7),3,5-triene	1160720: Inhibition of full length human NOX2 transfected in COS 22 cells assessed as inhibition of lithium dodecyl sulphate-stimulated ROS generation preincubated for 15 mins followed by lithium dodecyl sulphate challenge by cell-free assay in presence of NADPH	ic50	0.0300	uM
(2,3-dihydroxyphenyl)methyl 4-hydroxy-3-(hydroxymethyl)benzoate	2013304: Binding affinity to NOX2 (unknown origin) assessed as inhibition constant	ki	0.0540	uM
8-iodoniatricyclo[7.4.0.02,7]trideca-1(13),2,4,6,9,11-hexaene chloride	2013274: Inhibition of NOX2 in human PLB-985 cells assessed as inhibition of PMA-induced hydrogen peroxide production pretreated for 15 mins followed by PMA stimulation and measured after 10 mins by Amplex Red based fluorescence analysis	ic50	0.1000	uM
2-(3-benzyltriazolo[4,5-d]pyrimidin-7-yl)sulfanyl-1,3-benzoxazole	2013282: Inhibition of human NOX2 transfected in PLB-985 cells assessed as PMA-induced hydrogen peroxide pre-incubated for 10 and measured after 15 mins by Amplex-red based fluorescence assay	ic50	0.1000	uM
2-phenyl-1,2-benzoselenazol-3-one	2013277: Inhibition of human NOX2 expressed in HEK cells assessed as inhibition of ionomycin-induced hydrogen peroxide production pre-incubated for 15 mins followed by ionomycin stimulation and measured after 10 mins by Fluorescence polarization assay	ic50	0.3000	uM
4-(2-chlorophenyl)-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635430: Antagonist activity at human NOX2 in human polymorphonuclear cell membrane assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.3650	uM
4-(2-chlorophenyl)-12-oxa-4,5,9-triazatricyclo[7.4.0.02,6]trideca-1,6-diene-3,8-dione	635430: Antagonist activity at human NOX2 in human polymorphonuclear cell membrane assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.4330	uM
5-[2-[2-(2-aminoquinolin-5-yl)oxyethoxy]ethoxy]-7-phenylquinolin-2-amine	2020354: Inhibition of NOX-2 dependent superoxide generation in PMA-differentiated human PLB-985 cells incubated for 1 hr by WST-1 based assay	ic50	0.4900	uM
1-methyl-N-[3-(1-methyl-2,3-dihydroindol-6-yl)-1-propan-2-ylpyrrolo[2,3-b]pyridin-4-yl]pyrazole-4-sulfonamide	1920340: Inhibition of NOX2 (unknown origin)	ic50	0.5000	uM
4-(2-methoxyphenyl)-13-(pyridin-2-ylmethyl)-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635430: Antagonist activity at human NOX2 in human polymorphonuclear cell membrane assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.5100	uM
(5E)-3-cyclohexyl-5-[[2-hydroxy-4-[2-hydroxyethyl(methyl)amino]phenyl]methylidene]-1-methyl-2-sulfanylideneimidazolidin-4-one	1946378: Inhibition of human NOX2 assessed as reduction in ROS production using lucigenin as substrate in presence of NADPH by chemiluminescence based microplate reader analysis	ic50	0.5200	uM
5-phenyl-4-propyl-2-pyridin-2-yl-1H-pyrazol-3-one	2013289: Binding affinity to human NOX2 assessed as reduction in ROS production using lucigenin as substrate in presence of NADPH by chemiluminescence base assay	ki	0.5700	uM
(2R,4aS,6aR,6aS,14aS,14bR)-10-hydroxy-2,4a,6a,6a,9,14a-hexamethyl-11-oxo-1,3,4,5,6,13,14,14b-octahydropicene-2-carboxylic acid	2013274: Inhibition of NOX2 in human PLB-985 cells assessed as inhibition of PMA-induced hydrogen peroxide production pretreated for 15 mins followed by PMA stimulation and measured after 10 mins by Amplex Red based fluorescence analysis	ic50	0.5900	uM
13-benzyl-4-(2-methoxyphenyl)-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635430: Antagonist activity at human NOX2 in human polymorphonuclear cell membrane assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.6450	uM
(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-2-amino-5-carbamimidamidopentanoyl]amino]hexanoyl]amino]hexanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-sulfanylpropanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxybutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylpentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-4-methylpentanoic acid	2013314: Inhibition of NOX2 (unknown origin) transfected in HEK293 cells assessed as inhibition of hydrogen peroxide production pe-incubated for 15 mins and measured after 10 mins by Amplex Red based fluorescence analysis	ic50	0.7400	uM
4-(2-chlorophenyl)-13-[(4-methoxyphenyl)methyl]-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635430: Antagonist activity at human NOX2 in human polymorphonuclear cell membrane assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.7800	uM
4-(2-methoxyphenyl)-13-[(3-methoxyphenyl)methyl]-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635430: Antagonist activity at human NOX2 in human polymorphonuclear cell membrane assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.8200	uM
(5E)-5-[[4-(diethylamino)-2-hydroxyphenyl]methylidene]-1-methyl-3-phenyl-2-sulfanylideneimidazolidin-4-one	1946378: Inhibition of human NOX2 assessed as reduction in ROS production using lucigenin as substrate in presence of NADPH by chemiluminescence based microplate reader analysis	ic50	0.9100	uM
(5E)-3-cyclohexyl-5-[[4-[3-hydroxypropyl(methyl)amino]-2-methoxyphenyl]methylidene]-1-methyl-2-sulfanylideneimidazolidin-4-one	1946378: Inhibition of human NOX2 assessed as reduction in ROS production using lucigenin as substrate in presence of NADPH by chemiluminescence based microplate reader analysis	ic50	0.9900	uM
8-nitro-4-(3-nitrophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline	2013301: Inhibition of NOX2 (unknown origin) expressed in HEK293T cells assessed as inhibition of PMA-induced superoxide production preincubated for 15 mins followed by PMA stimulation and measured after 10 mins by Amplex-red based analysis	ic50	1.0000	uM
4-(2-chlorophenyl)-13-(furan-3-ylmethyl)-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635430: Antagonist activity at human NOX2 in human polymorphonuclear cell membrane assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	1.0200	uM
5-[2-[2-(2-aminoquinolin-5-yl)oxyethoxy]ethoxy]quinolin-2-amine	2020354: Inhibition of NOX-2 dependent superoxide generation in PMA-differentiated human PLB-985 cells incubated for 1 hr by WST-1 based assay	ic50	1.1000	uM
4-(2-chlorophenyl)-13-(pyridin-2-ylmethyl)-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635430: Antagonist activity at human NOX2 in human polymorphonuclear cell membrane assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	1.1400	uM
4-(2-chlorophenyl)-13-[(3-chlorophenyl)methyl]-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635430: Antagonist activity at human NOX2 in human polymorphonuclear cell membrane assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	1.1500	uM
4-(2-chlorophenyl)-13-[(2-chlorophenyl)methyl]-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635430: Antagonist activity at human NOX2 in human polymorphonuclear cell membrane assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	1.1600	uM
4-(2-chlorophenyl)-13-[(3-methoxyphenyl)methyl]-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635430: Antagonist activity at human NOX2 in human polymorphonuclear cell membrane assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	1.1950	uM
5-[2-[2-(2-aminoquinolin-5-yl)oxyethylamino]ethoxy]quinolin-2-amine	2020354: Inhibition of NOX-2 dependent superoxide generation in PMA-differentiated human PLB-985 cells incubated for 1 hr by WST-1 based assay	ic50	1.2000	uM
2-N-(3,4-dimethylphenyl)-6-[[4-(3-methoxyphenyl)piperazin-1-yl]methyl]-1,3,5-triazine-2,4-diamine	1917070: Inhibition of human NOX2	ic50	1.2500	uM
4-(2-chlorophenyl)-13-[(4-chlorophenyl)methyl]-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635430: Antagonist activity at human NOX2 in human polymorphonuclear cell membrane assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	1.2600	uM
tert-butyl 4-(2-chlorophenyl)-3,8-dioxo-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-13-carboxylate	635430: Antagonist activity at human NOX2 in human polymorphonuclear cell membrane assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	1.2800	uM
(5E)-5-[[4-(dimethylamino)-2-methoxyphenyl]methylidene]-1-methyl-3-phenyl-2-sulfanylideneimidazolidin-4-one	1946378: Inhibition of human NOX2 assessed as reduction in ROS production using lucigenin as substrate in presence of NADPH by chemiluminescence based microplate reader analysis	ic50	1.3100	uM
13-benzyl-4-(2-chlorophenyl)-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635430: Antagonist activity at human NOX2 in human polymorphonuclear cell membrane assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	1.3400	uM
4-(2-chlorophenyl)-13-(pyridin-3-ylmethyl)-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635430: Antagonist activity at human NOX2 in human polymorphonuclear cell membrane assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	1.3700	uM
(5E)-5-[[4-(diethylamino)-2-methoxyphenyl]methylidene]-1-methyl-3-phenyl-2-sulfanylideneimidazolidin-4-one	1946378: Inhibition of human NOX2 assessed as reduction in ROS production using lucigenin as substrate in presence of NADPH by chemiluminescence based microplate reader analysis	ic50	1.4700	uM
2-(2-chlorophenyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6-dione	537263: Inhibition of human NOX2 overexpressed in human PMN cell membrane assessed as ROS production by cell free assay in presence of NADPH	ki	1.5300	uM
(5E)-3-cyclohexyl-5-[[4-[2-hydroxyethyl(methyl)amino]-2-methoxyphenyl]methylidene]-1-methyl-2-sulfanylideneimidazolidin-4-one	1946378: Inhibition of human NOX2 assessed as reduction in ROS production using lucigenin as substrate in presence of NADPH by chemiluminescence based microplate reader analysis	ic50	1.5800	uM
5-[2-[2-(2-aminoquinolin-5-yl)oxyethyl-methylamino]ethoxy]quinolin-2-amine	2020354: Inhibition of NOX-2 dependent superoxide generation in PMA-differentiated human PLB-985 cells incubated for 1 hr by WST-1 based assay	ic50	1.6000	uM
(5E)-3-cyclohexyl-5-[[4-(diethylamino)-2-hydroxyphenyl]methylidene]-1-methyl-2-sulfanylideneimidazolidin-4-one	1946378: Inhibition of human NOX2 assessed as reduction in ROS production using lucigenin as substrate in presence of NADPH by chemiluminescence based microplate reader analysis	ic50	1.6600	uM
2-(2-chlorophenyl)-4-[3-(dimethylamino)phenyl]-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6-dione	2013291: Binding affinity to human NOX2 assessed as inhibition constant	ki	1.7500	uM
(5E)-5-[[4-(dimethylamino)phenyl]methylidene]-1-methyl-3-phenyl-2-sulfanylideneimidazolidin-4-one	1946378: Inhibition of human NOX2 assessed as reduction in ROS production using lucigenin as substrate in presence of NADPH by chemiluminescence based microplate reader analysis	ic50	1.7600	uM
4-(2-chlorophenyl)-13-[(2-methoxyphenyl)methyl]-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635430: Antagonist activity at human NOX2 in human polymorphonuclear cell membrane assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	1.7600	uM
(5E)-3-cyclohexyl-5-[[4-[2-hydroxyethyl(methyl)amino]phenyl]methylidene]-1-methyl-2-sulfanylideneimidazolidin-4-one	1946378: Inhibition of human NOX2 assessed as reduction in ROS production using lucigenin as substrate in presence of NADPH by chemiluminescence based microplate reader analysis	ic50	1.9000	uM
(5E)-3-cyclohexyl-5-[[4-(diethylamino)-2-methoxyphenyl]methylidene]-1-methyl-2-sulfanylideneimidazolidin-4-one	1946378: Inhibition of human NOX2 assessed as reduction in ROS production using lucigenin as substrate in presence of NADPH by chemiluminescence based microplate reader analysis	ic50	1.9500	uM
(5E)-5-[[4-(diethylamino)phenyl]methylidene]-1-methyl-3-phenyl-2-sulfanylideneimidazolidin-4-one	1946378: Inhibition of human NOX2 assessed as reduction in ROS production using lucigenin as substrate in presence of NADPH by chemiluminescence based microplate reader analysis	ic50	1.9600	uM
Naloxone	2013272: Inhibition of human NOX2 expressed in HEK293T cells assessed as inhibition of LPS-induced superoxide production pre-incubated for 45 mins and measure after 10 mins by chemiluminescence based analysis	ic50	1.9600	uM
12-benzyl-4-(2-chlorophenyl)-4,5,9,12-tetrazatricyclo[7.4.0.02,6]trideca-1,6-diene-3,8-dione;hydrochloride	635430: Antagonist activity at human NOX2 in human polymorphonuclear cell membrane assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	2.0150	uM
1-methyl-N-[3-(1-methyl-2,3-dihydroindol-6-yl)-1-propan-2-ylpyrrolo[2,3-b]pyridin-4-yl]pyrazole-3-sulfonamide	2013305: Inhibition of human NOX2	ic50	2.1000	uM
(5E)-3-cyclohexyl-5-[[4-[3-hydroxypropyl(methyl)amino]phenyl]methylidene]-1-methyl-2-sulfanylideneimidazolidin-4-one	1946378: Inhibition of human NOX2 assessed as reduction in ROS production using lucigenin as substrate in presence of NADPH by chemiluminescence based microplate reader analysis	ic50	2.4000	uM
(4S,4aR,7aS,12bR)-4a,9-dihydroxy-3-prop-2-enyl-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one	2013272: Inhibition of human NOX2 expressed in HEK293T cells assessed as inhibition of LPS-induced superoxide production pre-incubated for 45 mins and measure after 10 mins by chemiluminescence based analysis	ic50	2.5200	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
diphenyleneiodonium	decreases reaction, increases expression, affects cotreatment	3
Glucose	decreases reaction, increases activity, increases expression	3
Lipopolysaccharides	increases expression, increases reaction, decreases reaction	3
Tretinoin	affects cotreatment, increases expression	3
sodium arsenite	increases expression, decreases expression, affects reaction	2
acetovanillone	increases expression, affects cotreatment, decreases reaction, increases activity	2
2,3’,4,4’,5-pentachlorobiphenyl	increases expression, affects reaction, affects binding, increases reaction	2
Arsenic Trioxide	decreases expression, affects cotreatment, increases expression	2
Air Pollutants	affects expression, increases abundance, increases expression	2
Ethanol	increases expression	2
Hydrogen Peroxide	decreases reaction, increases expression	2
Melatonin	decreases reaction, increases expression	2
Nickel	increases expression	2
Ozone	increases abundance, affects cotreatment, increases expression, affects expression	2
Paraquat	affects cotreatment, decreases reaction, increases expression	2
1-Methyl-4-phenylpyridinium	increases expression, decreases reaction, decreases expression	2
Aflatoxin B1	decreases methylation, increases expression, decreases reaction	2
aristolochic acid I	decreases expression	1
diminazene aceturate	decreases expression	1
bisphenol A	increases expression, decreases reaction	1
geraniol	decreases reaction, increases expression	1
lead acetate	increases expression	1
rhodioloside	decreases expression, decreases reaction	1
palytoxin	increases expression	1
mevastatin	affects reaction, increases expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	affects binding, increases reaction	1
o,p’-DDT	increases expression, decreases reaction	1
sulforaphane	increases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	affects binding, increases reaction	1
vanadyl sulfate	decreases expression	1

ChEMBL screening assays

56 unique, capped per target: 54 binding, 1 unclassified, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1286960	Binding	Inhibition of human NOX2 overexpressed in human PMN cell membrane assessed as ROS production by cell free assay in presence of NADPH	First in class, potent, and orally bioavailable NADPH oxidase isoform 4 (Nox4) inhibitors for the treatment of idiopathic pulmonary fibrosis. — J Med Chem
CHEMBL1738361	Unclassified	PUBCHEM_BIOASSAY: Late stage results from the probe development effort to identify inhibitors of (NADPH oxidase 1) NOX1: Family selectivity: Set 2. (Class of assay: confirmatory) [Related pubchem assays (depositor defined):AID1792, AID1796,	PubChem BioAssay data set
CHEMBL1931063	Functional	Antagonist activity at human NOX2 in human polymorphonuclear cell membrane assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	Design, synthesis and biological activity of original pyrazolo-pyrido-diazepine, -pyrazine and -oxazine dione derivatives as novel dual Nox4/Nox1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

12 cell lines: 4 cancer cell line, 4 spontaneously immortalized cell line, 3 induced pluripotent stem cell, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8EG	Abcam HCT 116 CYBB KO	Cancer cell line	Male
CVCL_B8UJ	Abcam MCF-7 CYBB KO	Cancer cell line	Female
CVCL_B9GP	Abcam A-549 CYBB KO	Cancer cell line	Male
CVCL_C3HD	PLB-985 CYBB KO	Cancer cell line	Female
CVCL_C9Z7	CHCMUi002-A	Induced pluripotent stem cell	Male
CVCL_D9CU	Ubigene HEK293 CYBB KO	Transformed cell line	Female
CVCL_V183	iPSC-CGD2	Induced pluripotent stem cell	Male
CVCL_V184	iPSC-CGD3	Induced pluripotent stem cell	Male
CVCL_V327	CHO-91	Spontaneously immortalized cell line	Female
CVCL_V328	CHO-91-22	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00001317	PHASE4	COMPLETED	A Phase IV Study of Recombinant Human Gamma Interferon in Patients With Chronic Granulomatous Diseases of Childhood
NCT00023192	PHASE3	COMPLETED	Treatment of Chronic Granulomatous Disease With Allogeneic Stem Cell Transplantation Versus Standard of Care
NCT00033982	PHASE3	COMPLETED	Posaconazole to Treat Invasive Fungal Infections
NCT05345171	PHASE3	ACTIVE_NOT_RECRUITING	Clinical Study of DTX301 AAV-Mediated Gene Transfer for Ornithine Transcarbamylase (OTC) Deficiency
NCT00006417	PHASE2	COMPLETED	Modified Stem Cell Transplantation Procedure for Treating Chronic Granulomatous Disease
NCT00578643	PHASE2	COMPLETED	Matched Unrelated or Non-Genotype Identical Related Donor Transplantation For Chronic Granulomatous Disease
NCT00799071	PHASE2	COMPLETED	Pharmacokinetics of Posaconazole in Children With Chronic Granulomatous Disease (CGD)
NCT01821781	PHASE2	ACTIVE_NOT_RECRUITING	Immune Disorder HSCT Protocol
NCT01998633	PHASE2	COMPLETED	Reduced Intensity Conditioning for Hemophagocytic Syndromes or Selected Primary Immune Deficiencies (BMT CTN 1204)
NCT02512679	PHASE2	TERMINATED	Related Hematopoietic Stem Cell Transplantation (HSCT) for Genetic Diseases of Blood Cells
NCT03333486	PHASE2	TERMINATED	Fludarabine Phosphate, Cyclophosphamide, Total Body Irradiation, and Donor Stem Cell Transplant in Treating Patients With Blood Cancer
NCT03547830	PHASE2	UNKNOWN	Plerixafor/G-CSF as Additional Agents for Conditioning Before HSCT in CGD Patients
NCT03983837	PHASE2	COMPLETED	Elemental Diet for Treatment of Inflammatory Bowel Disease in Patients With Chronic Granulomatous Disease
NCT07284641	PHASE2	RECRUITING	Hematopoietic Stem Cell Transplantation (HSCT) for Common Variable Immunodeficiency (CVID) and Other Autoimmune Manifestations of Primary Immune Regulatory Disorders (PIRD)
NCT02871778	PHASE2	COMPLETED	Clearing Lungs With ENaC Inhibition in Primary Ciliary Dyskinesia
NCT07318974	PHASE2	ACTIVE_NOT_RECRUITING	Melatonin Therapy for Improving ICSI Outcomes in Women With Diminished Ovarian Reserve
NCT00718627	PHASE2	COMPLETED	Human Heterologous Liver Cells for Infusion in Children With Urea Cycle Disorders
NCT01599286	PHASE2	COMPLETED	Short-Term Outcome of N-Carbamylglutamate in the Treatment of Acute Hyperammonemia
NCT05526066	PHASE2	TERMINATED	Study for Adolescents and Adults With Ornithine Transcarbamylase Deficiency to Evaluate Safety and Tolerability of ARCT-810
NCT06488313	PHASE2	RECRUITING	A Study to Evaluate the Pharmacodynamics and Safety of ARCT-810 in Participants With OTCD
NCT00001476	PHASE1	COMPLETED	Gene Therapy for Chronic Granulomatous Diseases - Long-term Follow-up
NCT00001515	PHASE1	COMPLETED	Diagnostic Effectiveness of Virtual Bronchoscopy
NCT00001765	PHASE1	COMPLETED	Stem Cell Transplant Following Low-Intensity Chemotherapy to Treat Chronic Granulomatous Disease
NCT01917708	PHASE1	COMPLETED	Bone Marrow Transplant With Abatacept for Non-Malignant Diseases
NCT02609932	PHASE1	COMPLETED	Effect of IFN-γ on Innate Immune Cells
NCT05189925	PHASE1	RECRUITING	NADPH Oxidase Correction in mRNA-transfected Granulocyte-enriched Cells in Chronic Granulomatous Disease (CGD)
NCT05737485	PHASE1	COMPLETED	Study Evaluating the Safety and Tolerability of RCT1100 in Healthy and PCD Subjects
NCT06600425	PHASE1	COMPLETED	A Study to Assess the Safety, Tolerability, Ciliary Rescue, and Pharmacodynamics of RCT1100 in Adults With PCD
NCT06633757	PHASE1	COMPLETED	Study of Inhaled RCT1100 in Adults With PCD Caused by Pathogenic Mutations in the DNAI1 Gene to Measure Mucociliary Clearance
NCT04416126	PHASE1	COMPLETED	Safety, Tolerability and Pharmacokinetics of ARCT-810 in Healthy Adult Subjects
NCT04442347	PHASE1	COMPLETED	Phase 1b Study to Assess Safety, Tolerability, and Pharmacokinetics of ARCT-810 in Stable Adult Subjects With Ornithine Transcarbamylase Deficiency
NCT06247670	PHASE1	ACTIVE_NOT_RECRUITING	Study of CMP-CPS-001 in Healthy Volunteers and Participants With Abnormal Heterozygous OTC Genotype
NCT01381003	PHASE1/PHASE2	WITHDRAWN	Lentiviral Gene Therapy for X-Linked Chronic Granulomatous Disease (X-CGD)
NCT02234934	PHASE1/PHASE2	COMPLETED	Study of Gene Therapy Using a Lentiviral Vector to Treat X-linked Chronic Granulomatous Disease
NCT05600907	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Study to Assess the Use of JSP191 in Matched Unrelated Donor Transplantation for Chronic Granulomatous Disease (CGD)
NCT01953016	Not specified	COMPLETED	Participation in a Research Registry for Immune Disorders
NCT02233036	Not specified	COMPLETED	Evaluating the Transition From Pediatric to Adult Care Among Adolescents With Chronic Granulomatous Disease
NCT05546775	Not specified	UNKNOWN	Immunological Profile and Clinical Characteristics of Children Diagnosed With Chronic Granulomatous Disease
NCT03984890	PHASE2/PHASE3	COMPLETED	Vitamin D3 For CGD Patients With BCGosis/Itis
NCT00325078	PHASE1/PHASE2	TERMINATED	Infliximab to Treat Crohn’S-like Inflammatory Bowel Disease in Chronic Granulomatous Disease