KDM5B

Summary

KDM5B (lysine demethylase 5B, HGNC:18039) is a protein-coding gene on chromosome 1q32.1, encoding Lysine-specific demethylase 5B (Q9UGL1). Histone demethylase that demethylates ‘Lys-4’ of histone H3, thereby playing a central role in histone code.

This gene encodes a lysine-specific histone demethylase that belongs to the jumonji/ARID domain-containing family of histone demethylases. The encoded protein is capable of demethylating tri-, di- and monomethylated lysine 4 of histone H3. This protein plays a role in the transcriptional repression or certain tumor suppressor genes and is upregulated in certain cancer cells. This protein may also play a role in genome stability and DNA repair. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 10765 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual disability, autosomal recessive 65 (Strong, GenCC) — +4 more curated relationships
• Clinical variants (ClinVar): 547 total — 35 pathogenic, 54 likely-pathogenic
• Phenotypes (HPO): 37
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• Transcription factor: yes — 39 downstream targets (CollecTRI)
• MANE Select transcript: NM_006618

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18039
Approved symbol	KDM5B
Name	lysine demethylase 5B
Location	1q32.1
Locus type	gene with protein product
Status	Approved
Aliases	RBBP2H1A, PLU-1, CT31, PPP1R98
Ensembl gene	ENSG00000117139
Ensembl biotype	protein_coding
OMIM	605393
Entrez	10765

Gene structure

Transcript identifiers

Ensembl transcripts: 47 — 23 protein_coding, 16 retained_intron, 5 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay

ENST00000235790, ENST00000367264, ENST00000367265, ENST00000456180, ENST00000467487, ENST00000470573, ENST00000472822, ENST00000491153, ENST00000498276, ENST00000602511, ENST00000647657, ENST00000647747, ENST00000647754, ENST00000647757, ENST00000648056, ENST00000648099, ENST00000648338, ENST00000648354, ENST00000648469, ENST00000648473, ENST00000648676, ENST00000648738, ENST00000648744, ENST00000648958, ENST00000649089, ENST00000649200, ENST00000649230, ENST00000649321, ENST00000649339, ENST00000649388, ENST00000649400, ENST00000649542, ENST00000649770, ENST00000649929, ENST00000650368, ENST00000650417, ENST00000650422, ENST00000650493, ENST00000650506, ENST00000650569, ENST00000939933, ENST00000939934, ENST00000939935, ENST00000939936, ENST00000939937, ENST00000939938, ENST00000949534

RefSeq mRNA: 4 — MANE Select: NM_006618 NM_001314042, NM_001347591, NM_001399817, NM_006618

CCDS: CCDS30974, CCDS81417, CCDS91143, CCDS91144

Canonical transcript exons

ENST00000367265 — 27 exons

Exon	Start	End
ENSE00001074885	202729707	202730027
ENSE00001074894	202741367	202741722
ENSE00001074896	202742655	202742805
ENSE00001074904	202746142	202746323
ENSE00001074909	202745858	202745982
ENSE00001074919	202742391	202742505
ENSE00001196719	202752905	202753067
ENSE00001297765	202764049	202764145
ENSE00001299608	202760415	202760573
ENSE00001316733	202762699	202762808
ENSE00001324008	202766926	202767060
ENSE00001643352	202750659	202750778
ENSE00001857675	202724495	202729173
ENSE00002326684	202740674	202740812
ENSE00002420574	202748945	202749139
ENSE00002428160	202736213	202736392
ENSE00003468369	202773118	202773288
ENSE00003489061	202735429	202735587
ENSE00003492455	202730909	202731063
ENSE00003497489	202731828	202731939
ENSE00003508573	202755271	202755452
ENSE00003590841	202733401	202733886
ENSE00003591120	202756358	202756516
ENSE00003677819	202758391	202758510
ENSE00003680270	202774613	202774735
ENSE00003681946	202777017	202777094
ENSE00003834207	202808102	202808421

Expression profiles

Bgee: expression breadth ubiquitous, 272 present calls, max score 98.96.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 81.5327 / max 1200.8819, expressed in 1819 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
16736	60.4808	1813
16738	11.5035	1782
16737	9.1816	1759
16735	0.1544	37
16733	0.1461	15
16732	0.0464	8
16734	0.0199	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	98.96	gold quality
male germ cell	CL:0000015	98.22	gold quality
left testis	UBERON:0004533	97.81	gold quality
right testis	UBERON:0004534	97.61	gold quality
testis	UBERON:0000473	97.18	gold quality
cortical plate	UBERON:0005343	96.71	gold quality
ganglionic eminence	UBERON:0004023	96.57	gold quality
ventricular zone	UBERON:0003053	96.14	gold quality
colonic epithelium	UBERON:0000397	96.13	gold quality
embryo	UBERON:0000922	95.84	gold quality
adrenal tissue	UBERON:0018303	95.59	gold quality
adult organism	UBERON:0007023	95.00	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	94.99	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	94.65	gold quality
tongue squamous epithelium	UBERON:0006919	94.40	gold quality
upper leg skin	UBERON:0004262	94.10	gold quality
cartilage tissue	UBERON:0002418	94.08	gold quality
stromal cell of endometrium	CL:0002255	93.15	gold quality
lower esophagus mucosa	UBERON:0035834	93.03	gold quality
esophagus squamous epithelium	UBERON:0006920	92.84	gold quality
mammalian vulva	UBERON:0000997	92.72	gold quality
epithelium of esophagus	UBERON:0001976	92.48	gold quality
gingiva	UBERON:0001828	92.43	gold quality
skin of abdomen	UBERON:0001416	92.25	gold quality
gingival epithelium	UBERON:0001949	92.21	gold quality
skin of leg	UBERON:0001511	92.17	gold quality
bone marrow cell	CL:0002092	92.07	gold quality
squamous epithelium	UBERON:0006914	92.02	gold quality
zone of skin	UBERON:0000014	91.87	gold quality
buccal mucosa cell	CL:0002336	91.57	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-137537	yes	24.22
E-CURD-112	yes	9.67
E-CURD-114	yes	9.44
E-MTAB-7303	no	1544.24
E-GEOD-99795	no	99.01
E-GEOD-93593	no	10.51
E-GEOD-125970	no	3.19
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

39 targets.

Target	Regulation
ABCA4
ACTBL2
BMI1
BRCA2
CALML5
CAV1
CCND1
CDC14A
CDKN1A
CDKN1B
CFC1
CHST3
CLDN1
DNAJB12
ELF3
ESRP1
FGFR1
FOXA1	Activation
FOXG1	Unknown
FST
GHRHR
HEXIM1
KDM4A
KDM5B
KRT16
MCAT
ME3
MIR17HG
MIR31
MIRLET7E

Upstream regulators (CollecTRI, top): EPAS1, HIF1A, KDM5B, MYCN, SP1

miRNA regulators (miRDB)

186 targeting KDM5B, 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-3613-3P	100.00	76.36	7965
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-MIR-98-3P	100.00	74.08	3907
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-548J-3P	99.94	72.61	4881

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• results suggest that the PLU-1 protein may belong to the class of testis/cancer antigens (PMID:12237901)
• BF-1 and PAX9 interact with PLU-1 via a novel conserved sequence motif (Ala-X-Ala-Ala-X-Val-Pro-X4-Val-Pro-X8-Pro, termed the VP motif) (PMID:12657635)
• PLU-1-mediated H3K4 demethylase activity plays an important role in the proliferative capacity of breast cancer cells through repression of tumor suppressor genes. (PMID:17363312)
• Results show that both JARID1B and HDAC4 expressed in breast cancers. (PMID:17373667)
• Results identify the target genes regulated by PLU-1/JARID1B, and show that cells overexpressing PLU-1/JARID1B have an impaired G(2)/M checkpoint. (PMID:17709396)
• data support an anti-tumorigenic role of RBP2-H1/JARID1B in melanocytic cells. (PMID:17973255)
• JARID1B was identified as a demethylase capable of removing three methyl groups from histone H3 lysine 4 and up-regulated in prostate cancer. (PMID:18048344)
• 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)
• Microarray expression analysis indicated that E2F1 and E2F2 are downstream genes in the KDM5B pathway. (PMID:20226085)
• The results from this study demonstrate that the flexible loop L1 of the human JARID1B ARID domain has a crucial role in DNA-binding activity. (PMID:20403335)
• Knockdown of JARID1B leads to an initial acceleration of tumor growth followed by exhaustion which suggests that the JARID1B-positive subpopulation is essential for continuous tumor growth. (PMID:20478252)
• PARP-1 regulates chromatin structure and transcription through a KDM5B-dependent pathway. (PMID:20832725)
• JARID1B is the first TIEG1 corepressor identified, explaining how TIEG1 represses transcription through inducing histone H3 lysine 4 demethylation, which may be important for TIEG1 function in both normal and cancer cells. (PMID:20863814)
• there is a significant increase in the percentage of circulating CD8+ T cells that are specific for two of three investigated JARID1B HLA-A*0201 peptides (PMID:21105039)
• JARID1B is widely expressed in estrogen receptor+ breast cancers and breast cancer cell lines (PMID:21369698)
• crystal of JARID1B belonged to space group P4(3), with unit-cell parameters a = 51.7, b = 51.7, c = 36.2 A (PMID:21821892)
• JARID1B & LSD1 act in a sequential, coordinated manner to demethylate H3K4. JARID1B represses CCL14 expression, suppressing the angiogenic and metastatic potential of breast cancer cells in vivo. (PMID:21937684)
• JARID1B demethylase contributes to tumor cell proliferation through the epigenetic repression of a tumor suppressor miR (PMID:21969366)
• By displacing histone H3K4 demethylase PLU-1, FOXP3 increases both H4K16 acetylation and H3K4 trimethylation at the FOXP3-associated chromatins of multiple FOXP3-activated genes. (PMID:22152480)
• demonstrated that while TFAP2C and Myc can downregulate the CDKN1A promoter independently, KDM5B acts as a corepressor dependent on the other two proteins (PMID:22371483)
• JARID1B and PHF2 are overexpressed in esophageal squamous cell carcinoma (ESCC) and they may play crucial roles in the course of ESCC initiation and/or progression (PMID:22534467)
• Jarid1a/b-mediated H3K4 demethylation contributes to silencing of retinoblastoma target genes in senescent cells, suggesting a mechanism by which retinoblastoma triggers gene silencing. (PMID:22615382)
• This study demonstrates that JARID1B is expressed by uveal melanoma cells. (PMID:22669717)
• Contrary to earlier reports, this study shows enhanced expression of JARID1B by melanoma cells and indicates that such an enhancement may be an early event in the disease progression and is not correlated with melanoma invasiveness. (PMID:23262439)
• JARID1B plays a role in colorectal cancer maintenance. (PMID:23354547)
• analysis of small molecule inhibitors of Jumonji AT-rich interactive domain 1B (JARID1B) histone demethylase by a sensitive high throughput screen (PMID:23408432)
• these results indicate that KDM5B represses Cx26 expression in the bladder cancer development. (PMID:23579952)
• A novel role of KDM5B histone lysine demethylase in epithelial-mesenchymal transition, which may contribute to malignant progression of cancer. (PMID:23759590)
• KDM5B is SUMOylated at lysine residues 242 and 278 and that the ectopic expression of the hPC2 SUMO E3 ligase enhances this SUMOylation. (PMID:23970103)
• The first and third, but not the second, PHD fingers of KDM5B possess histone binding activities. (PMID:24412361)
• Our findings suggest that Myc-mediated transcriptional repression of JARID1B counterintuitively inhibits Myc-regulated cell proliferation and potentially tumorigenesis. (PMID:24481781)
• Our results provide global and functional insight into the role of KDM5B in regulating H3K4 methylation marks near promoters, gene bodies, and enhancers in ES cells and during differentiation. (PMID:24495580)
• Study reports that KDM5B (PLU-1/JARID1B), a histone lysine demethylase of Jumonji family, associates with PRC2 and colocalizes with PRC2 in nuclear bodies, and their physical association is dependent on direct interaction between KDM5B and the SUZ12 component of PRC2. (PMID:24619877)
• Our results suggest that KDM5B is a bona fide DNA damage response protein and indicate that KDM5B is an important genome caretaker and a critical regulator of genome stability. (PMID:24778210)
• Integrated JARID1B chromatin binding, H3K4 methylation, and expression profiles suggest a key function for JARID1B in luminal cell-specific expression programs. (PMID:24937458)
• Data show that double mutations on the residues in the interface (L325A/D328A) decreases the histone H3 H3K4me2/3 demethylation activity of lysine (K)-specific demethylase 5B (KDM5B). (PMID:24952722)
• KDM5B promoted glioma proliferation partly via regulation of the expression of p21. (PMID:25450384)
• correlation between JARID1B level and chemotherapy resistance was observed in patients with epithelial ovarian cancer (odds ratio (OR) 36.81, 95% CI 4.84-280.11, P < 0.001). (PMID:25663457)
• This study revealed hyper JARID1B expression and hypo histone H3 lysine 4 tri-methylation in mantle cell lymphoma (PMID:25755704)
• PLU-1/JARID1B represents a candidate proliferation biomarker for HNSCC diagnosis and treatment. (PMID:25777981)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	kdm5bb	ENSDARG00000003098
danio_rerio	kdm5ba	ENSDARG00000057093
mus_musculus	Kdm5b	ENSMUSG00000042207
rattus_norvegicus	Kdm5b	ENSRNOG00000060544
drosophila_melanogaster	Kdm5	FBGN0031759
caenorhabditis_elegans		WBGENE00004319

Paralogs (10): JARID2 (ENSG00000008083), KDM5D (ENSG00000012817), KDM4A (ENSG00000066135), KDM5A (ENSG00000073614), KDM4C (ENSG00000107077), KDM5C (ENSG00000126012), KDM4B (ENSG00000127663), KDM4D (ENSG00000186280), KDM4E (ENSG00000235268), KDM4F (ENSG00000255855)

Protein

Protein identifiers

Lysine-specific demethylase 5B — Q9UGL1 (reviewed: Q9UGL1)

Alternative names: Cancer/testis antigen 31, Histone demethylase JARID1B, Jumonji/ARID domain-containing protein 1B, PLU-1, Retinoblastoma-binding protein 2 homolog 1, [histone H3]-trimethyl-L-lysine(4) demethylase 5B

All UniProt accessions (18): A0A3B3IS31, A0A3B3IS40, A0A3B3ISE6, A0A3B3ISK2, A0A3B3IT25, A0A3B3IT51, A0A3B3IT85, A0A3B3ITA8, A0A3B3ITA9, A0A3B3ITE7, A0A3B3ITJ3, A0A3B3ITJ7, A0A3B3ITN3, A0A3B3ITR1, A0A3B3ITR3, B3KV94, Q9UGL1, R4GN45

UniProt curated annotations — full annotation on UniProt →

Function. Histone demethylase that demethylates ‘Lys-4’ of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 ‘Lys-9’ or H3 ‘Lys-27’. Demethylates trimethylated, dimethylated and monomethylated H3 ‘Lys-4’. Acts as a transcriptional corepressor for FOXG1B and PAX9. Favors the proliferation of breast cancer cells by repressing tumor suppressor genes such as BRCA1 and HOXA5. In contrast, may act as a tumor suppressor for melanoma. Represses the CLOCK-BMAL1 heterodimer-mediated transcriptional activation of the core clock component PER2.

Subunit / interactions. Interacts with FOXG1B, PAX9, MYC, MYCN and RB1. Interacts with HDAC1, HDAC4, HDAC5 and HDAC7. Interacts (via PHD-type 1 zinc finger) with histone H3 unmodified at ‘Lys-4’; the interaction is inhibited when histone H3 is methylated at ‘Arg-2’ or ‘Lys-4’.

Subcellular location. Nucleus.

Tissue specificity. Ubiquitously expressed, with highest levels in testis. Down-regulated in melanoma and glioblastoma. Up-regulated in breast cancer (at protein level).

Disease relevance. Intellectual developmental disorder, autosomal recessive 65 (MRT65) [MIM:618109] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRT65 patients have moderate to severe intellectual disability, developmental delay, and facial dysmorphism. Camptodactyly is present in some patients. The disease may be caused by variants affecting the gene represented in this entry.

Activity regulation. Several specific inhibitors are being developed and tested. The inhibitor KDOAM-25 inhibits its demethylase activity, resulting to cell cycle arrest in myeloma cells.

Cofactor. Binds 1 Fe(2+) ion per subunit.

Domain organisation. Both the JmjC domain and the JmjN domain are required for enzymatic activity. However ARID and PHD-type 1 domain are not required for activity per se but contributed to recognition of the H3(1-21)K4me2 substrate peptide. The 2 first PHD-type zinc finger domains are required for transcription repression activity.

Similarity. Belongs to the JARID1 histone demethylase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UGL1-1	1	yes
Q9UGL1-2	2

RefSeq proteins (4): NP_001300971, NP_001334520, NP_001386746, NP_006609* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001606	ARID_dom	Domain
IPR001965	Znf_PHD	Domain
IPR003347	JmjC_dom	Domain
IPR003349	JmjN	Domain
IPR004198	Znf_C5HC2	Domain
IPR011011	Znf_FYVE_PHD	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR013637	Lys_sp_deMease-like_dom	Domain
IPR019786	Zinc_finger_PHD-type_CS	Conserved_site
IPR019787	Znf_PHD-finger	Domain
IPR036431	ARID_dom_sf	Homologous_superfamily
IPR047978	KDM5B_PHD1	Domain
IPR047979	KDM5B_PHD3	Domain
IPR047981	KDM5B_ARID	Domain
IPR048615	KDM5_C-hel	Domain

Pfam: PF00628, PF01388, PF02373, PF02375, PF02928, PF08429, PF21323

Enzyme classification (BRENDA):

• EC 1.14.11.67 — [histone H3]-trimethyl-L-lysine4 demethylase (BRENDA: 13 organisms, 78 substrates, 122 inhibitors, 22 Km, 20 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
[ACETYLATED HISTONE H3 21MER]-N6,N6,N6-TRIMETHYL	0.0168–0.0955	2
[ACETYLATED HISTONE H3 21MER]-N6,N6-DIMETHYL-L-L	0.0547–0.229	2
[HISTONE H3]-N6,N6-DIMETHYL-L-LYSINE4	0.0107–0.0128	2
[HISTONE H3 N-TERMINAL 13MER] N6,N6,N6-TRIMETHYL	0.489	1
[HISTONE H3 N-TERMINAL 18MER MUTANT K14A/R17A/K1	0.514	1
[HISTONE H3 N-TERMINAL 18MER MUTANT K14AC/K18AC]	0.249	1
[HISTONE H3 N-TERMINAL 18MER] N6,N6,N6-TRIMETHYL	0.0623	1
[HISTONE H3 N-TERMINAL 21MER MUTANT K9A] N6,N6,N	0.0219	1
[HISTONE H3 N-TERMINAL 21MER MUTANT Q5A] N6,N6,N	0.4152	1
[HISTONE H3 N-TERMINAL 21MER MUTANT R2A] N6,N6,N	0.1536	1
[HISTONE H3 N-TERMINAL 21MER MUTANT R8A] N6,N6,N	0.0551	1
[HISTONE H3 N-TERMINAL 21MER MUTANT T3A] N6,N6,N	0.009	1
[HISTONE H3 N-TERMINAL 21MER MUTANT T6A] N6,N6,N	0.0965	1
[HISTONE H3 N-TERMINAL 21MER MUTANT T6S] N6,N6,N	0.0147	1
[HISTONE H3 N-TERMINAL 21MER MUTANT T6V] N6,N6,N	0.0394	1

Catalyzed reactions (Rhea), 1 shown:

• N(6),N(6),N(6)-trimethyl-L-lysyl(4)-[histone H3] + 3 2-oxoglutarate + 3 O2 = L-lysyl(4)-[histone H3] + 3 formaldehyde + 3 succinate + 3 CO2 (RHEA:60208)

UniProt features (128 total): strand 29, helix 28, mutagenesis site 20, sequence conflict 9, cross-link 8, turn 7, binding site 7, modified residue 4, zinc finger region 4, domain 3, compositionally biased region 3, sequence variant 2, region of interest 2, chain 1, splice variant 1

Structure

Experimental structures (PDB)

56 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
5FYZ	X-RAY DIFFRACTION	1.75
5FZ8	X-RAY DIFFRACTION	1.86
5FYB	X-RAY DIFFRACTION	1.87
5FYT	X-RAY DIFFRACTION	1.87
5FYV	X-RAY DIFFRACTION	1.87
6EIU	X-RAY DIFFRACTION	1.88
5FYS	X-RAY DIFFRACTION	1.89
5A3T	X-RAY DIFFRACTION	1.9
5FZI	X-RAY DIFFRACTION	1.95
5FZG	X-RAY DIFFRACTION	1.96
5FZF	X-RAY DIFFRACTION	1.97
5A3N	X-RAY DIFFRACTION	2
5A3W	X-RAY DIFFRACTION	2
5A3P	X-RAY DIFFRACTION	2.01
5FZE	X-RAY DIFFRACTION	2.02
5FY9	X-RAY DIFFRACTION	2.03
5FZC	X-RAY DIFFRACTION	2.05
5FZD	X-RAY DIFFRACTION	2.05
5FZK	X-RAY DIFFRACTION	2.05
6EK6	X-RAY DIFFRACTION	2.05
5FYU	X-RAY DIFFRACTION	2.06
5FZ9	X-RAY DIFFRACTION	2.06
6EJ0	X-RAY DIFFRACTION	2.06
5FZ4	X-RAY DIFFRACTION	2.07
6EJ1	X-RAY DIFFRACTION	2.07
5FZH	X-RAY DIFFRACTION	2.09
5FZA	X-RAY DIFFRACTION	2.1
5A1F	X-RAY DIFFRACTION	2.1
5FY4	X-RAY DIFFRACTION	2.1
6EIN	X-RAY DIFFRACTION	2.11

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UGL1-F1	72.52	0.24

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 (7): 425; 499; 501; 507; 509; 517; 587

Post-translational modifications (12): 832, 986, 1328, 1456, 148, 204, 209, 242, 274, 278, 769, 1450

Mutagenesis-validated functional residues (20):

Position	Phenotype
308	slightly decreases interaction with histone h3. decreases by 21% demethylase activity and repression of tumor suppressor
309	no effect on interaction with histone h3.
310	slightly decreases interaction with histone h3.
310	no effect on interaction with histone h3.
311	no effect on interaction with histone h3.
321	decreases interaction with histone h3.
322	no effect on interaction with histone h3.
324	no effect on interaction with histone h3.
325	abolishes interaction with histone h3. decreases by 44% demethylase activity and repression of tumor suppressor genes ex
326	no effect on interaction with histone h3.
328	almost abolishes interaction with histone h3. decreases by 44% demethylase activity and repression of tumor suppressor g
332	no effect on interaction with histone h3.
333	no effect on interaction with histone h3.
334	no effect on interaction with histone h3.
335	slightly impairs transcription repression ability.
345	no effect on interaction with histone h3.
351	abolishes interaction with histone h3. decreases by 28% demethylase activity and repression of tumor suppressor genes ex
499–501	abolishes lysine-specific histone demethylase activity.
499	abolishes lysine-specific histone demethylase activity.
1200	impairs transcription repression ability and interaction with hdac4.

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-3214842	HDMs demethylate histones
R-HSA-8866911	TFAP2 (AP-2) family regulates transcription of cell cycle factors
R-HSA-9821002	Chromatin modifications during the maternal to zygotic transition (MZT)
R-HSA-1266738	Developmental Biology
R-HSA-212436	Generic Transcription Pathway
R-HSA-3247509	Chromatin modifying enzymes
R-HSA-4839726	Chromatin organization
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8864260	Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors
R-HSA-9816359	Maternal to zygotic transition (MZT)

MSigDB gene sets: 460 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GCACCTT_MIR18A_MIR18B, GOBP_SINGLE_FERTILIZATION, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOBP_LENS_FIBER_CELL_DIFFERENTIATION, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_MAMMARY_GLAND_MORPHOGENESIS, GOBP_GLAND_MORPHOGENESIS, GOBP_REGULATION_OF_MAMMARY_GLAND_EPITHELIAL_CELL_PROLIFERATION, MODULE_255, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOBP_RESPONSE_TO_PEPTIDE, GOBP_MAMMARY_GLAND_EPITHELIUM_DEVELOPMENT, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_GROWTH

GO Biological Process (17): chromatin remodeling (GO:0006338), regulation of DNA-templated transcription (GO:0006355), single fertilization (GO:0007338), post-embryonic development (GO:0009791), positive regulation of gene expression (GO:0010628), positive regulation of mammary gland epithelial cell proliferation (GO:0033601), cellular response to fibroblast growth factor stimulus (GO:0044344), negative regulation of DNA-templated transcription (GO:0045892), rhythmic process (GO:0048511), branching involved in mammary gland duct morphogenesis (GO:0060444), mammary duct terminal end bud growth (GO:0060763), response to fungicide (GO:0060992), uterus morphogenesis (GO:0061038), lens fiber cell differentiation (GO:0070306), cellular response to leukemia inhibitory factor (GO:1990830), regulation of estradiol secretion (GO:2000864), chromatin organization (GO:0006325)

GO Molecular Function (14): nucleic acid binding (GO:0003676), DNA binding (GO:0003677), transcription corepressor activity (GO:0003714), zinc ion binding (GO:0008270), histone demethylase activity (GO:0032452), histone H3K4 demethylase activity (GO:0032453), histone H3K4me/H3K4me2/H3K4me3 demethylase activity (GO:0034647), histone binding (GO:0042393), sequence-specific double-stranded DNA binding (GO:1990837), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), metal ion binding (GO:0046872), dioxygenase activity (GO:0051213), histone H3 demethylase activity (GO:0141052)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Chromatin modifying enzymes	1
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	1
Maternal to zygotic transition (MZT)	1
RNA Polymerase II Transcription	1
Chromatin organization	1
Gene expression (Transcription)	1
Generic Transcription Pathway	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
DNA-templated transcription	2
regulation of gene expression	2
mammary gland duct morphogenesis	2
binding	2
chromatin organization	1
regulation of RNA biosynthetic process	1
fertilization	1
multicellular organism development	1
multicellular organismal process	1
gene expression	1
positive regulation of macromolecule biosynthetic process	1
mammary gland epithelial cell proliferation	1
regulation of mammary gland epithelial cell proliferation	1
positive regulation of epithelial cell proliferation	1
positive regulation of developmental process	1
positive regulation of multicellular organismal process	1
cellular response to growth factor stimulus	1
response to fibroblast growth factor	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
biological_process	1
branching morphogenesis of an epithelial tube	1
developmental growth involved in morphogenesis	1
response to toxic substance	1
response to antibiotic	1
developmental process involved in reproduction	1
animal organ morphogenesis	1
uterus development	1
lens development in camera-type eye	1
epithelial cell differentiation	1
cellular response to cytokine stimulus	1
response to leukemia inhibitory factor	1
estradiol secretion	1
regulation of steroid hormone secretion	1
cellular component organization	1
nucleic acid binding	1
transcription coregulator activity	1
negative regulation of DNA-templated transcription	1
transition metal ion binding	1

Protein interactions and networks

STRING

3528 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KDM5B	KDM1A	O60341	983
KDM5B	HDAC1	Q13547	961
KDM5B	RCOR1	Q9UKL0	865
KDM5B	EZH2	Q15910	823
KDM5B	FOXG1	P55315	774
KDM5B	TFAP2C	Q92754	771
KDM5B	MYC	P01106	762
KDM5B	RBBP5	Q15291	731
KDM5B	CBX3	Q13185	723
KDM5B	ESR1	P03372	713
KDM5B	AR	P10275	712
KDM5B	EHMT2	Q96KQ7	693
KDM5B	PAX9	P55771	684
KDM5B	KDM6B	O15054	682
KDM5B	ERBB2	P04626	672

IntAct

49 interactions, top by confidence:

A	B	Type	Score
YWHAG	SHTN1	psi-mi:“MI:0914”(association)	0.560
YWHAB	SHTN1	psi-mi:“MI:0914”(association)	0.530
YWHAE	SHTN1	psi-mi:“MI:0914”(association)	0.530
YWHAZ	SHTN1	psi-mi:“MI:0914”(association)	0.530
FAM90A1	RFPL4A	psi-mi:“MI:0914”(association)	0.530
KDM5B	CTCF	psi-mi:“MI:0915”(physical association)	0.520
CTCF	KDM5B	psi-mi:“MI:0915”(physical association)	0.520
KDM5B	H3C1	psi-mi:“MI:0871”(demethylation reaction)	0.440
PPP1CA	KDM5B	psi-mi:“MI:0407”(direct interaction)	0.440
HTT		psi-mi:“MI:0914”(association)	0.350
PRPF4	PFDN6	psi-mi:“MI:0914”(association)	0.350
KDM4A	PIPSL	psi-mi:“MI:0914”(association)	0.350
KDM5B	PLPBP	psi-mi:“MI:0914”(association)	0.350
YWHAH	SHTN1	psi-mi:“MI:0914”(association)	0.350
YWHAQ	SHTN1	psi-mi:“MI:0914”(association)	0.350
H2BC21	SMCHD1	psi-mi:“MI:0914”(association)	0.350
HMGN5	SMCHD1	psi-mi:“MI:0914”(association)	0.350
NUCKS1	SMARCA5	psi-mi:“MI:0914”(association)	0.350
TSPYL6	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
SNAPC4	PIK3C2A	psi-mi:“MI:0914”(association)	0.350
AFG2B	MMP24OS	psi-mi:“MI:0914”(association)	0.350
KDM5B	TGFB2	psi-mi:“MI:0914”(association)	0.350
KDM5B	FST	psi-mi:“MI:0914”(association)	0.350
	KDM5B	psi-mi:“MI:0914”(association)	0.350

BioGRID (145): KDM5B (Affinity Capture-MS), CDX2 (Affinity Capture-Western), CBX4 (Affinity Capture-Western), FOXG1 (Two-hybrid), KDM5B (Affinity Capture-MS), PAX9 (Two-hybrid), KDM5B (Synthetic Growth Defect), KDM5B (Affinity Capture-Western), KDM5B (Affinity Capture-MS), KDM5B (Affinity Capture-MS), KDM5B (Affinity Capture-RNA), KMT2A (Negative Genetic), KDM5B (Affinity Capture-MS), KDM5B (Co-localization), KDM5B (Affinity Capture-RNA)

ESM2 similar proteins: A0A0R4IB93, A1A5P5, A1Z7K9, A2XDG4, A3AF13, A3KMI0, A6QR55, B2GUZ1, D3ZJ96, F6V6I0, F6Z5C0, F8VPZ3, O22207, P29375, P35123, P51784, Q09879, Q13107, Q14149, Q2HJE4, Q30DN6, Q3UXZ9, Q3V0C5, Q5D006, Q5I043, Q5RCD3, Q5ZID5, Q5ZM45, Q62240, Q6NZP1, Q76LT8, Q80U87, Q80Y84, Q86UV5, Q8BWR4, Q8NFA0, Q8R5C8, Q8R5H1, Q93Y01, Q96RU2

Diamond homologs: A0A1W2PPD8, A1A5Q5, A1YVX4, B2RXH2, C0SUT9, F4I240, F4I6G4, F4KIX0, O64752, O75164, O94953, P29375, P39956, P41229, P41230, P47156, Q03833, Q10RP4, Q1LVC2, Q23541, Q30DN6, Q336N8, Q38JA7, Q3U2K5, Q3UXZ9, Q53WJ1, Q5F3R2, Q5N712, Q5RD88, Q5XUN4, Q61T02, Q62240, Q62315, Q6B0I6, Q6BDA0, Q6IQX0, Q80Y84, Q8BW72, Q8GUI6, Q8VCD7

SIGNOR signaling

17 interactions.

A	Effect	B	Mechanism
KDM5B	“up-regulates activity”	PAX9	binding
KDM5B	“up-regulates activity”	FOXG1	binding
KDM5B	“up-regulates activity”	CBX4	binding
KDM5B	“up-regulates activity”	H3C1	demethylation
KDM5B	“up-regulates activity”	H3-4	demethylation
KDM5B	“up-regulates activity”	H3-3A	demethylation
KDM5B	“up-regulates activity”	“Histone H3”	demethylation
HIF1A	“up-regulates quantity by expression”	KDM5B	“transcriptional regulation”
PARP1	“up-regulates activity”	KDM5B	relocalization
RNF4	“down-regulates quantity by destabilization”	KDM5B	sumoylation
“Polycomb repressive complex 2”	“down-regulates activity”	KDM5B
EPAS1	“up-regulates quantity by expression”	KDM5B	“transcriptional regulation”
CDK1	“down-regulates activity”	KDM5B	phosphorylation
HEXIM1	“up-regulates activity”	KDM5B	relocalization
KDM5B	“down-regulates quantity by repression”	SOX2	“transcriptional regulation”
KDM5B	“down-regulates quantity by repression”	NANOG	“transcriptional regulation”
2-oxoglutarate(2-)	“up-regulates activity”	KDM5B	“chemical activation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 47 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
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	146.9×	2e-12
Activation of BAD and translocation to mitochondria	6	142.8×	1e-10
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	126.0×	3e-10
Activation of BH3-only proteins	6	93.1×	2e-09
RHO GTPases activate PKNs	6	59.5×	2e-08
Intrinsic Pathway for Apoptosis	6	54.9×	3e-08
FOXO-mediated transcription	5	52.5×	7e-07
SARS-CoV-1-host interactions	7	38.4×	2e-08

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	42.6×	3e-05
intracellular protein localization	8	19.5×	4e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	35
Likely pathogenic	54
Uncertain significance	310
Likely benign	63
Benign	17

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1319834	NM_006618.5(KDM5B):c.3424-2A>G	Pathogenic
1686735	NM_006618.5(KDM5B):c.2265C>A (p.Tyr755Ter)	Pathogenic
1694541	NM_006618.5(KDM5B):c.2198+1G>C	Pathogenic
1711236	NM_006618.5(KDM5B):c.1454del (p.Pro485fs)	Pathogenic
1992395	NM_006618.5(KDM5B):c.453_454del (p.Trp152fs)	Pathogenic
2199844	NM_006618.5(KDM5B):c.2264dup (p.Tyr755Ter)	Pathogenic
2265951	NM_006618.5(KDM5B):c.906del (p.Ala303fs)	Pathogenic
2269169	NM_006618.5(KDM5B):c.814_817dup (p.Met273fs)	Pathogenic
2299096	NM_006618.5(KDM5B):c.390dup (p.Phe131fs)	Pathogenic
2309603	NM_006618.5(KDM5B):c.1538G>A (p.Trp513Ter)	Pathogenic
2395103	NM_006618.5(KDM5B):c.2950C>T (p.Arg984Ter)	Pathogenic
2500707	NM_006618.5(KDM5B):c.2117del (p.Cys706fs)	Pathogenic
2584391	NM_006618.5(KDM5B):c.2830dup (p.Leu944fs)	Pathogenic
2639803	NM_006618.5(KDM5B):c.1354G>T (p.Glu452Ter)	Pathogenic
3113853	NM_006618.5(KDM5B):c.1558dup (p.Tyr520fs)	Pathogenic
3250989	NM_006618.5(KDM5B):c.2377_2380del (p.Asp793fs)	Pathogenic
3337448	NM_006618.5(KDM5B):c.3566_3567insTT (p.Met1189fs)	Pathogenic
3341020	NM_006618.5(KDM5B):c.941T>G (p.Leu314Ter)	Pathogenic
3366608	NM_006618.5(KDM5B):c.954_957del (p.Asn319fs)	Pathogenic
3376907	NM_006618.5(KDM5B):c.326_327del (p.Lys109fs)	Pathogenic
3377007	NM_006618.5(KDM5B):c.1997_2001del (p.Arg666fs)	Pathogenic
3379373	NM_006618.5(KDM5B):c.685C>T (p.Arg229Ter)	Pathogenic
3602227	NM_006618.5(KDM5B):c.1539-1G>A	Pathogenic
3898526	NM_006618.5(KDM5B):c.2358del (p.Glu787fs)	Pathogenic
4531371	NM_006618.5(KDM5B):c.2446C>T (p.Gln816Ter)	Pathogenic
4688410	NM_006618.5(KDM5B):c.4198C>T (p.Arg1400Ter)	Pathogenic
4813831	NM_006618.5(KDM5B):c.4422T>G (p.Tyr1474Ter)	Pathogenic
4822496	NM_006618.5(KDM5B):c.3133C>T (p.Arg1045Ter)	Pathogenic
4845460	NM_006618.5(KDM5B):c.394C>T (p.Gln132Ter)	Pathogenic
560601	c.2475-2A-G	Pathogenic

SpliceAI

4501 predictions. Top by Δscore:

Variant	Effect	Δscore
1:202730904:CTCA:C	donor_loss	1.0000
1:202730905:TCACC:T	donor_loss	1.0000
1:202730906:CACCT:C	donor_loss	1.0000
1:202730907:A:AC	donor_gain	1.0000
1:202730908:C:CC	donor_gain	1.0000
1:202730908:C:CG	donor_loss	1.0000
1:202730908:CCTT:C	donor_gain	1.0000
1:202731059:AACAC:A	acceptor_gain	1.0000
1:202731060:ACAC:A	acceptor_gain	1.0000
1:202731061:CAC:C	acceptor_gain	1.0000
1:202731061:CACC:C	acceptor_gain	1.0000
1:202731062:AC:A	acceptor_gain	1.0000
1:202731063:CC:C	acceptor_gain	1.0000
1:202731063:CCTG:C	acceptor_loss	1.0000
1:202731064:C:CC	acceptor_gain	1.0000
1:202731064:CT:C	acceptor_loss	1.0000
1:202731075:C:CT	acceptor_gain	1.0000
1:202731843:A:AT	donor_gain	1.0000
1:202735424:CATA:C	donor_gain	1.0000
1:202735427:A:AC	donor_gain	1.0000
1:202735428:C:CC	donor_gain	1.0000
1:202735428:CAG:C	donor_gain	1.0000
1:202741718:AGATC:A	acceptor_gain	1.0000
1:202741719:GATC:G	acceptor_gain	1.0000
1:202741720:ATC:A	acceptor_gain	1.0000
1:202741720:ATCC:A	acceptor_loss	1.0000
1:202741721:TC:T	acceptor_gain	1.0000
1:202741721:TCC:T	acceptor_loss	1.0000
1:202741722:CC:C	acceptor_gain	1.0000
1:202741723:C:CC	acceptor_gain	1.0000

AlphaMissense

10134 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:202729122:A:G	C1517R	1.000
1:202729157:C:G	C1505S	1.000
1:202729158:A:G	C1505R	1.000
1:202729158:A:T	C1505S	1.000
1:202729165:C:A	W1502C	1.000
1:202729165:C:G	W1502C	1.000
1:202729745:A:G	C1487R	1.000
1:202742730:A:G	L800P	1.000
1:202745909:A:G	W758R	1.000
1:202745909:A:T	W758R	1.000
1:202746197:A:G	C715R	1.000
1:202746257:A:G	C695R	1.000
1:202746264:A:C	C692W	1.000
1:202746266:A:G	C692R	1.000
1:202749080:A:C	F627L	1.000
1:202749080:A:T	F627L	1.000
1:202749082:A:G	F627L	1.000
1:202750661:A:G	W607R	1.000
1:202750661:A:T	W607R	1.000
1:202750677:G:C	N601K	1.000
1:202750677:G:T	N601K	1.000
1:202750690:G:T	A597D	1.000
1:202750695:A:C	N595K	1.000
1:202750695:A:T	N595K	1.000
1:202750702:C:A	G593V	1.000
1:202750703:C:G	G593R	1.000
1:202750707:G:C	N591K	1.000
1:202750707:G:T	N591K	1.000
1:202750710:A:C	F590L	1.000
1:202750710:A:T	F590L	1.000

dbSNP variants (sampled 300 via entrez): RS1000008229 (1:202766739 G>A), RS1000018840 (1:202766866 G>A,C), RS1000030971 (1:202790858 C>T), RS1000049378 (1:202807388 C>G,T), RS1000099443 (1:202778475 T>C), RS1000101531 (1:202727362 G>A,C,T), RS1000109851 (1:202773434 T>C), RS1000125633 (1:202798438 T>C), RS1000195916 (1:202741027 C>T), RS1000233194 (1:202747318 A>C), RS1000240745 (1:202808157 T>A), RS1000271395 (1:202725969 G>A,C,T), RS1000278269 (1:202760211 G>A,C), RS1000299280 (1:202760764 T>G), RS1000300975 (1:202789457 G>A)

Disease associations

OMIM: gene MIM:605393 | disease phenotypes: MIM:618109, MIM:600057, MIM:607086, MIM:619681

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, autosomal recessive 65	Strong	Autosomal recessive
neurodevelopmental disorder	Strong	Semidominant
autosomal recessive non-syndromic intellectual disability	Supportive	Autosomal recessive
Tourette syndrome	No Known Disease Relationship	Unknown

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
intellectual disability	Moderate	AR

Mondo (11): intellectual disability, autosomal recessive 65 (MONDO:0020850), intellectual disability (MONDO:0001071), neurodevelopmental disorder (MONDO:0700092), autism spectrum disorder (MONDO:0005258), diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype (MONDO:0858939), bladder exstrophy-epispadias-cloacal exstrophy complex (MONDO:0700039), familial thoracic aortic aneurysm and aortic dissection (MONDO:0019625), cleft palate (MONDO:0016064), dystonia, early-onset, and/or spastic paraplegia (MONDO:0859215), Tourette syndrome (MONDO:0007661), autosomal recessive non-syndromic intellectual disability (MONDO:0019502)

Orphanet (5): Classic bladder exstrophy (Orphanet:93930), Familial thoracic aortic aneurysm and aortic dissection (Orphanet:91387), Cleft palate (Orphanet:2014), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

37 total (30 of 37 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000233	Thin vermilion border
HP:0000268	Dolichocephaly
HP:0000319	Smooth philtrum
HP:0000321	Square face
HP:0000377	Abnormal pinna morphology
HP:0000414	Bulbous nose
HP:0000426	Prominent nasal bridge
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000508	Ptosis
HP:0000545	Myopia
HP:0000718	Aggressive behavior
HP:0000750	Delayed speech and language development
HP:0001263	Global developmental delay
HP:0001338	Partial agenesis of the corpus callosum
HP:0001631	Atrial septal defect
HP:0001684	Secundum atrial septal defect
HP:0002066	Gait ataxia
HP:0002079	Hypoplasia of the corpus callosum
HP:0002317	Unsteady gait
HP:0002342	Moderate intellectual disability
HP:0002558	Supernumerary nipple
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0005487	Prominent metopic ridge

GWAS associations

0 associations (top):

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D002972	Cleft Palate	C05.500.460.185; C05.660.207.540.460.185; C07.320.440.185; C07.465.525.185; C07.650.500.460.185; C07.650.525.185; C16.131.621.207.540.460.185; C16.131.850.500.460.185; C16.131.850.525.185
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
D005879	Tourette Syndrome	C10.228.140.079.898; C10.228.662.825.800; C10.574.500.850; C16.320.400.820; F03.625.992.850

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL3774295 (SINGLE PROTEIN), CHEMBL4296073 (PROTEIN FAMILY), CHEMBL6066024 (PROTEIN-PROTEIN INTERACTION), CHEMBL6193826 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 49,542 (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
CHEMBL145	CAFFEIC ACID	3	36,305
CHEMBL51085	EBSELEN	3	13,237

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — 1.14.11.- Histone demethylases

Most potent curated ligand interactions (6 total), top 6:

Ligand	Action	Affinity	Parameter
KDOAM25	Inhibition	7.72	pIC50
GSK-J1	Inhibition	6.77	pIC50
KDM5 inhibitor N71	Irreversible inhibition	6.66	pIC50
Compound 9 [doi:10.26434/chemrxiv.7072592.v1]	Inhibition	6.52	pIC50
PBIT	Inhibition	5.52	pIC50
GSK-J4	Inhibition	5.01	pIC50

Binding affinities (BindingDB)

344 measured of 653 human assays (653 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
4’-(phenethylcarbamoyl)-[2,2’-bipyridine]-4-carboxylic acid (N3)	IC50	61 nM
2-{1-[2-(2-ethoxyphenyl)ethyl]-1H-imidazol-4-yl}-4- [5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl]pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
4-[5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl]-2- (1-{2-[2-(trifluoromethyl)phenyl]ethyl}-1H- imidazol-4-yl)pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
2-[1-(2-methyl-1-phenylpropyl)-1H-imidazol-4-yl]-4- [5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl]pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
2-{1-[2-(2-chloro-6-fluorophenyl)ethyl]-1H- imidazol-4-yl}-4-[5-(trifluoromethyl)-1H-1,2,3- triazol-4-yl]pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
2-{1-[(2,3-dihydro-1H-inden-1-yl)methyl]-1H- imidazol-4-yl}-4-[5-(trifluoromethyl)-1H-1,2,3- triazol-4-yl]pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
4-[5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl]-2-(1-{2- [4-(trifluoromethyl)phenyl]ethyl}-1H-imidazol-4- yl)pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
2-{1-[2-(4-ethylphenyl)ethyl]-1H-imidazol-4-yl}-4- [5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl]pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
2-{1-[2-(4-tert-butylphenyl)ethyl]-1H-imidazol-4- yl}-4-[5-(trifluoromethyl)-1H-1,2,3-triazol-4- yl]pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
2-{1-[(5-fluoro-1,2,3,4-tetrahydronaphthalen-1- yl)methyl]-1H-imidazol-4-yl}-4-[5-(trifluoromethyl)- 1H-1,2,3,-triazol-4-yl]pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
2-{1-[(6-fluoro-1,2,3,4-tetrahydronaphthalen-1- yl)methyl]-1H-imidazol-4-yl}-4-[5-(trifluoromethyl)- 1H-1,2,3-triazol-4-yl]pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
2-{1-[(7-fluoro-1,2,3,4-tetrahydronaphthalen-1- yl)methyl]-1H-imidazol-4-yl}-4-[5-(trifluoromethyl)- 1H-1,2,3-triazol-4-yl]pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
2-{1-[(7-methyl-1,2,3,4-tetrahydronaphthalen-1- yl)methyl]-1H-imidazol-4-yl}-4-[5-(trifluoromethyl)- 1H-1,2,3-triazol-4-yl]pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
2-{1-[(5-methoxy-1,2,3,4-tetrahydronaphthalen-1- yl)methyl]-1H-imidazol-4-yl}-4-[5-(trifluoromethyl)- 1H-1,2,3-triazol-4-yl]pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
2-{1-[(6-methoxy-1,2,3,4-tetrahydronaphthalen-1- yl)methyl]-1H-imidazol-4-yl}-4-[5-(trifluoromethyl)- 1H-1,2,3-triazol-4-yl]pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
2-{1-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-1- yl)methyl]-1H-imidazol-4-yl}-4-[5-(trifluoromethyl)- 1H-1,2,3-triazol-4-yl]pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
2-{1-[(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)methyl]-1H-imidazol-4-yl}-4-[5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl]pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
2-(1-{[2-(2,2,2- trifluoroethoxy)phenyl]methyl}-1H- imidazol-4-yl)-4-[5-(trifluoromethyl)-1H- 1,2,3-triazol-4-yl]pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
2-[5-[(4-chloro-2-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid	IC50	550 nM	US-9908865: Histone demethylase inhibitors
3-((1-methyl-1Hpyrrolo[2,3-b]pyridin-3-yl)amino)isonicotinic acid (N12)	IC50	550 nM	US-10336727: Histone demethylase inhibitors
2-(5-hydroxy-3-methyl-1H- pyrazol-1-yl)isonicotinic acid	IC50	550 nM	US-9908865: Histone demethylase inhibitors
2-(5-hydroxy-3,4- dimethyl-1H-pyrazol-1- yl)isonicotinic acid	IC50	550 nM	US-9908865: Histone demethylase inhibitors
2-(5-hydroxy-3-methyl-4- phenyl-1H-pyrazol-1- yl)isonicotinic acid	IC50	550 nM	US-9908865: Histone demethylase inhibitors
2-(5-hydroxy-3-propyl-1H- pyrazol-1-yl)isonicotinic acid	IC50	550 nM	US-9908865: Histone demethylase inhibitors
2-(5-hydroxy-1H-pyrazol-1- yl)isonicotinic acid	IC50	550 nM	US-9908865: Histone demethylase inhibitors
2-(5-p-tolyl-1H-pyrazol-1- yl)isonicotinic acid	IC50	550 nM	US-9908865: Histone demethylase inhibitors
2-(5-m-tolyl-1H-pyrazol-1- yl)isonicotinic acid	IC50	550 nM	US-9908865: Histone demethylase inhibitors
2-(5-(2,4-difluorophenyl)-1H- pyrazol-1-yl)isonicotinic acid	IC50	550 nM	US-9908865: Histone demethylase inhibitors
2-(5-(3,4-difluorophenyl)-1H- pyrazol-1-yl)isonicotinic acid	IC50	550 nM	US-9908865: Histone demethylase inhibitors
2-(5-(3-fluorophenyl)-1H-pyrazol- 1-yl)isonicotinic acid	IC50	550 nM	US-9908865: Histone demethylase inhibitors
2-(5-(3-hydroxyphenyl)-1H- pyrazol-1-yl)isonicotinic acid	IC50	550 nM	US-9908865: Histone demethylase inhibitors
2-(5-(4-hydroxyphenyl)-1H- pyrazol-1-yl)isonicotinic acid	IC50	550 nM	US-9908865: Histone demethylase inhibitors
2-(5-(3-hydroxy-4-methylphenyl)- 1H-pyrazol-1-yl)isonicotinic acid	IC50	550 nM	US-9908865: Histone demethylase inhibitors
2-(5-methyl-1H-pyrazol-1- yl)isonicotinic acid	IC50	550 nM	US-9908865: Histone demethylase inhibitors
2-(3-phenethyl-1H-pyrazol-1- yl)isonicotinic acid	IC50	550 nM	US-9908865: Histone demethylase inhibitors
2-(5-(benzyloxy)-3-methyl-1H- pyrazol-1-yl)isonicotinic acid	IC50	550 nM	US-9908865: Histone demethylase inhibitors
2-{5-[(4-methoxybenzyl)oxy]-1H- pyrazol-1-yl}pyridine-4- carboxylic acid	IC50	550 nM	US-9908865: Histone demethylase inhibitors
2-[5-(1H-indazol-6-ylmethoxy)- 1H-pyrazol-1-yl]pyridine-4- carboxylic acid	IC50	550 nM	US-9908865: Histone demethylase inhibitors
2-{5-[(1-methyl-1H-indazol-6- yl)methoxy]-1H-pyrazol-1- yl}pyridine-4-carboxylic acid	IC50	550 nM	US-9908865: Histone demethylase inhibitors
2-{5-[(3,4- difluorobenzyl)oxy]-1H- pyrazol-1-yl}pyridine-4- carboxylic acid	IC50	550 nM	US-9908865: Histone demethylase inhibitors
2-(5-{[4- (trifluoromethyl)benzyl]oxy}- 1H-pyrazol-1-yl)pyridine-4- carboxylic acid	IC50	550 nM	US-9908865: Histone demethylase inhibitors
2-[5-(pyridin-3-ylmethoxy)-1H- pyrazol-1-yl]pyridine-4-carboxylic acid	IC50	550 nM	US-9908865: Histone demethylase inhibitors
2-{5-[(4,4- difluorocyclohexyl)methoxy]-1H- pyrazol-1-yl}pyridine-4- carboxylic acid	IC50	550 nM	US-9908865: Histone demethylase inhibitors
2-{5-[(4-cyclopropylbenzyl)oxy]- 1H-pyrazol-1-yl}pyridine-4- carboxylic acid	IC50	550 nM	US-9908865: Histone demethylase inhibitors
2-[5-[1-(4- fluorophenyl)ethoxy]pyrazol-1- yl]pyridine-4-carboxylic acid	IC50	550 nM	US-9908865: Histone demethylase inhibitors
2-[5-[(4-fluorophenyl)methoxy]-4- methylpyrazol-1-yl]pyridine-4- carboxylic acid	IC50	550 nM	US-9908865: Histone demethylase inhibitors
2-[4-ethyl-5-[(4- fluorophenyl)methoxy]pyrazol-1- yl]pyridine-4-carboxylic acid	IC50	550 nM	US-9908865: Histone demethylase inhibitors
2-[5-[(2,4- difluorophenyl)methoxy]pyrazol- 1-yl]pyridine-4-carboxylic acid	IC50	550 nM	US-9908865: Histone demethylase inhibitors
2-[5-[(3,4- dichlorophenyl)methoxy]pyrazol- 1-yl]pyridine-4-carboxylic acid	IC50	550 nM	US-9908865: Histone demethylase inhibitors

ChEMBL bioactivities

1171 potent at pChembl≥5 of 1232 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.22	IC50	0.6	nM	CHEMBL4229271
9.00	IC50	1	nM	CHEMBL4225358
9.00	IC50	1	nM	CHEMBL4228806
9.00	IC50	1	nM	CHEMBL4228292
9.00	Ki	1	nM	CHEMBL4567766
9.00	Ki	1	nM	CHEMBL4438830
8.87	IC50	1.34	nM	CHEMBL4542928
8.70	IC50	2	nM	CHEMBL4226978
8.70	IC50	2	nM	CHEMBL3786952
8.70	Ki	2	nM	CHEMBL3774537
8.70	Ki	2	nM	CHEMBL4573390
8.70	IC50	1.99	nM	CHEMBL5569973
8.65	IC50	2.23	nM	CHEMBL3787669
8.52	IC50	3	nM	CHEMBL4227237
8.52	Ki	3	nM	CHEMBL4447515
8.52	IC50	3	nM	CHEMBL4454253
8.52	IC50	3.05	nM	CHEMBL5568891
8.40	IC50	4	nM	CHEMBL4225013
8.40	IC50	4	nM	CHEMBL4228610
8.40	IC50	4	nM	CHEMBL3785832
8.40	IC50	4	nM	CHEMBL4228087
8.40	IC50	4	nM	CHEMBL4228546
8.40	IC50	4	nM	CHEMBL4229264
8.40	IC50	4	nM	CHEMBL4227526
8.40	Ki	4	nM	CHEMBL4585876
8.40	IC50	4	nM	CHEMBL3787669
8.40	IC50	4	nM	CHEMBL5285949
8.33	IC50	4.7	nM	CHEMBL3785583
8.30	IC50	5	nM	CHEMBL4449500
8.29	IC50	5.08	nM	CHEMBL5929387
8.29	IC50	5.08	nM	CHEMBL5931047
8.29	IC50	5.08	nM	CHEMBL5822004
8.29	IC50	5.08	nM	CHEMBL6044046
8.29	IC50	5.08	nM	CHEMBL6008477
8.29	IC50	5.08	nM	CHEMBL6050056
8.29	IC50	5.08	nM	CHEMBL5934920
8.29	IC50	5.08	nM	CHEMBL6049443
8.29	IC50	5.08	nM	CHEMBL6056294
8.29	IC50	5.08	nM	CHEMBL5759098
8.28	IC50	5.22	nM	CHEMBL6016801
8.28	IC50	5.29	nM	CHEMBL5744580
8.24	IC50	5.73	nM	CHEMBL5991906
8.24	IC50	5.74	nM	CHEMBL5943639
8.24	IC50	5.77	nM	CHEMBL5746747
8.23	IC50	5.83	nM	CHEMBL5810916
8.22	IC50	6	nM	CHEMBL4225515
8.22	IC50	6	nM	CHEMBL4438830
8.20	IC50	6.32	nM	CHEMBL5592899
8.20	IC50	6.28	nM	CHEMBL5751730
8.20	IC50	6.27	nM	CHEMBL6048186

PubChem BioAssay actives

432 with measured affinity, of 747 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
2-[5-[(4-cyanophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid	1391728: Inhibition of KDM5B (unknown origin) preincubated with enzyme	ic50	0.0006	uM
8-[4-[2-[4-[3-[2-(dimethylamino)ethyl]phenyl]piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1556144: Binding affinity to KDM5B (unknown origin)	ki	0.0010	uM
8-[4-[2-[4-(3-pyridin-3-ylphenyl)piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1556144: Binding affinity to KDM5B (unknown origin)	ki	0.0010	uM
2-(5-phenylmethoxypyrazol-1-yl)pyridine-4-carboxylic acid	1391728: Inhibition of KDM5B (unknown origin) preincubated with enzyme	ic50	0.0010	uM
2-[5-[(4-chloro-2-methoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid	1391728: Inhibition of KDM5B (unknown origin) preincubated with enzyme	ic50	0.0010	uM
2-[4-[2-(dimethylamino)ethyl]-5-[(4-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid	1391728: Inhibition of KDM5B (unknown origin) preincubated with enzyme	ic50	0.0010	uM
5-[4-[2-[hexyl(methyl)amino]ethyl]phenyl]-7-oxo-6-propan-2-yl-1H-pyrazolo[1,5-a]pyrimidine-3-carbonitrile	1624961: Inhibition of human N-terminal FLAG/His-tagged KDM5B (2 to 751 residues) expressed in baculovirus infected Sf9 insect cells using H3(1-21)K4(Me3)-GGK(Biotin)/2-OG as substrate measured after 1 hr by Alphalisa assay	ic50	0.0013	uM
8-[4-[2-[4-(3-chlorophenyl)piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1556144: Binding affinity to KDM5B (unknown origin)	ki	0.0020	uM
8-[4-[2-[4-(3-chlorophenyl)-4-methylpiperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1556144: Binding affinity to KDM5B (unknown origin)	ki	0.0020	uM
2-[[[2-[2-[butyl(methyl)amino]ethyl-ethylamino]-2-oxoethyl]amino]methyl]pyridine-4-carboxylic acid	2106948: Inhibition of KDM5B (unknown origin) incubated for 2 hrs by Alphascreen assay	ic50	0.0020	uM
2-[5-[(4-chloro-2-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid	1391728: Inhibition of KDM5B (unknown origin) preincubated with enzyme	ic50	0.0020	uM
2-[5-[(4-bromophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid	1391728: Inhibition of KDM5B (unknown origin) preincubated with enzyme	ic50	0.0020	uM
2-[[[2-[2-(dimethylamino)ethyl-ethylamino]-2-oxoethyl]amino]methyl]pyridine-4-carboxylic acid	2106948: Inhibition of KDM5B (unknown origin) incubated for 2 hrs by Alphascreen assay	ic50	0.0022	uM
8-[4-[2-[4-(3-fluorophenyl)piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1556144: Binding affinity to KDM5B (unknown origin)	ki	0.0030	uM
7-oxo-5-phenyl-6-propan-2-yl-1H-pyrazolo[1,5-a]pyrimidine-3-carbonitrile	1627992: Inhibition of KDM5B (unknown origin) using ART(Kme3)QTARKSTGGKAPRKQLA-NovaTagPEG-biotin/2-OG as substrate/co-factor by TR-FRET assay	ic50	0.0030	uM
2-[5-[(4-ethylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid	1391728: Inhibition of KDM5B (unknown origin) preincubated with enzyme	ic50	0.0030	uM
2-[[[2-[ethyl-[2-[methyl(propan-2-yl)amino]ethyl]amino]-2-oxoethyl]amino]methyl]pyridine-4-carboxylic acid	2106948: Inhibition of KDM5B (unknown origin) incubated for 2 hrs by Alphascreen assay	ic50	0.0031	uM
8-[4-[2-[4-[4-[2-(dimethylamino)ethyl]phenyl]piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1556144: Binding affinity to KDM5B (unknown origin)	ki	0.0040	uM
(E)-4-(dimethylamino)-N-[3-[[methyl-[2-[1-(4-oxo-3H-pyrido[3,4-d]pyrimidin-8-yl)pyrazol-4-yl]ethyl]amino]methyl]phenyl]but-2-enamide	1928196: Inhibition of KDM5B (unknown origin)	ic50	0.0040	uM
2-[5-[(4-methoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid	1391728: Inhibition of KDM5B (unknown origin) preincubated with enzyme	ic50	0.0040	uM
2-[5-[(4-chlorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid	1391728: Inhibition of KDM5B (unknown origin) preincubated with enzyme	ic50	0.0040	uM
2-[5-[(4-chloro-2-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid	1391728: Inhibition of KDM5B (unknown origin) preincubated with enzyme	ic50	0.0040	uM
2-[5-[(4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid	1391728: Inhibition of KDM5B (unknown origin) preincubated with enzyme	ic50	0.0040	uM
2-[5-[(4-chloro-2-ethoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid	1391728: Inhibition of KDM5B (unknown origin) preincubated with enzyme	ic50	0.0040	uM
2-[5-[(4-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid	1391728: Inhibition of KDM5B (unknown origin) preincubated with enzyme	ic50	0.0040	uM
2-[5-[(4-chloro-2-phenylmethoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid	1391728: Inhibition of KDM5B (unknown origin) preincubated with enzyme	ic50	0.0040	uM
5-(1-tert-butylpyrazol-4-yl)-7-oxo-6-propan-2-yl-1H-pyrazolo[1,5-a]pyrimidine-3-carbonitrile	1627220: Inhibition of KDM5B (unknown origin)	ic50	0.0047	uM
8-[4-(2-spiro[1,2-dihydroindene-3,4’-piperidine]-1’-ylethyl)pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1556132: Inhibition of full length human KDM5B assessed as decrease in demethylation of substrate using peptide ARTK(me3)QTARKSTGGKAPRKQLA-GGK-biotin as substrate and 0.25 uM 2OG as cosubstrate pre-incubated for 10 mins before substrate addition followed by centrifugation for 1 min and measured after 15 mins by AlphaScreen assay	ic50	0.0050	uM
2-[5-[[4-chloro-2-(cyclopropylmethoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid	1391728: Inhibition of KDM5B (unknown origin) preincubated with enzyme	ic50	0.0060	uM
2-[[[2-[ethyl-[2-[methyl(propyl)amino]ethyl]amino]-2-oxoethyl]amino]methyl]pyridine-4-carboxylic acid	2106948: Inhibition of KDM5B (unknown origin) incubated for 2 hrs by Alphascreen assay	ic50	0.0063	uM
2-[[[2-[ethyl-[2-[ethyl(methyl)amino]ethyl]amino]-2-oxoethyl]amino]methyl]pyridine-4-carboxylic acid	2106948: Inhibition of KDM5B (unknown origin) incubated for 2 hrs by Alphascreen assay	ic50	0.0069	uM
2-chloro-N-[2-[4-(3-cyano-7-oxo-6-propan-2-yl-1H-pyrazolo[1,5-a]pyrimidin-5-yl)pyrazol-1-yl]ethyl]acetamide	1928196: Inhibition of KDM5B (unknown origin)	ic50	0.0070	uM
4-[1-[2-[1-(4-oxo-3H-pyrido[3,4-d]pyrimidin-8-yl)pyrazol-4-yl]ethyl]piperidin-4-yl]benzonitrile	1282544: Inhibition of KDM5B (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0070	uM
2-[5-[(4-cyclopropylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid	1391728: Inhibition of KDM5B (unknown origin) preincubated with enzyme	ic50	0.0080	uM
2-[[[2-[2-[benzyl(methyl)amino]ethyl-ethylamino]-2-oxoethyl]amino]methyl]pyridine-4-carboxylic acid	2106948: Inhibition of KDM5B (unknown origin) incubated for 2 hrs by Alphascreen assay	ic50	0.0084	uM
N-[3-[[methyl-[2-[1-(4-oxo-3H-pyrido[3,4-d]pyrimidin-8-yl)pyrazol-4-yl]ethyl]amino]methyl]phenyl]prop-2-enamide	1928196: Inhibition of KDM5B (unknown origin)	ic50	0.0090	uM
2-chloro-N-[2-[4-(3-cyano-7-oxo-6-propan-2-yl-1H-pyrazolo[1,5-a]pyrimidin-5-yl)phenoxy]ethyl]acetamide	1928196: Inhibition of KDM5B (unknown origin)	ic50	0.0090	uM
8-[4-[2-[4-(4-methoxyphenyl)piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1282544: Inhibition of KDM5B (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0100	uM
8-[4-[2-[4-(4-methylsulfonylphenyl)piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1282544: Inhibition of KDM5B (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0100	uM
2-chloro-N-[3-[[methyl-[2-[1-(4-oxo-3H-pyrido[3,4-d]pyrimidin-8-yl)pyrazol-4-yl]ethyl]amino]methyl]phenyl]acetamide	1928196: Inhibition of KDM5B (unknown origin)	ic50	0.0100	uM
8-[4-[2-[4-(2,4-difluorophenyl)piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1282544: Inhibition of KDM5B (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0110	uM
8-[4-[2-[4-[3-(2-morpholin-4-ylethyl)phenyl]piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1556103: Inhibition of KDM5B (unknown origin) assessed as decrease in demethylation of substrate using peptide (H3(1-21)K4-Me3-GGKBiotin) as substrate and 2OG as cosubstrate pre-incubated for 15 mins before substrate addition followed by centrifugation for 15 secs and measured after 20 mins by Alphascreen assay	ic50	0.0120	uM
8-[4-[2-[4-[3-(pyrrolidin-1-ylmethyl)phenyl]piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1556103: Inhibition of KDM5B (unknown origin) assessed as decrease in demethylation of substrate using peptide (H3(1-21)K4-Me3-GGKBiotin) as substrate and 2OG as cosubstrate pre-incubated for 15 mins before substrate addition followed by centrifugation for 15 secs and measured after 20 mins by Alphascreen assay	ic50	0.0120	uM
2-(2-amino-1,3-thiazol-4-yl)pyridine-4-carboxylic acid	1282544: Inhibition of KDM5B (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0120	uM
8-[4-[2-[4-[(4-chlorophenyl)methyl]piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1282544: Inhibition of KDM5B (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0140	uM
8-[4-[2-[4-(3,5-dichlorophenyl)piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1282544: Inhibition of KDM5B (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0140	uM
8-[4-[2-(4-pyridin-4-ylpiperidin-1-yl)ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1282544: Inhibition of KDM5B (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0150	uM
8-[4-[2-[4-[[4-(trifluoromethyl)phenyl]methyl]piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1282544: Inhibition of KDM5B (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0150	uM
8-[4-[2-[4-[(3,4-dichlorophenyl)methyl]piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1282544: Inhibition of KDM5B (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0150	uM
8-[4-[2-[4-(1,3-benzodioxol-5-ylmethyl)piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1282544: Inhibition of KDM5B (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0160	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, increases methylation, decreases expression, increases expression	3
(+)-JQ1 compound	increases expression	3
Tretinoin	increases expression, decreases expression	3
Resveratrol	affects cotreatment, decreases expression, increases expression	2
Valproic Acid	affects expression, decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
FR900359	affects phosphorylation	1
Batroxase, Bothrops atrox	increases expression	1
TAK-243	affects sumoylation	1
bufotalin	decreases expression	1
triphenyl phosphate	affects expression	1
uranyl acetate	affects expression	1
beta-lapachone	increases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
fumonisin B1	increases expression	1
tamibarotene	affects expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
deguelin	decreases expression	1
fenpyroximate	decreases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	decreases expression	1
pyrimidifen	decreases expression	1
ICG 001	decreases expression	1
abrine	increases expression	1
pyrachlostrobin	decreases expression	1
jinfukang	decreases expression	1
picoxystrobin	decreases expression	1
MK-8776	increases expression	1

ChEMBL screening assays

146 unique, capped per target: 146 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3776211	Binding	Inhibition of KDM5B (unknown origin) using biotin-H3K4me3 as substrate at 100 uM preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay relative to control	8-Substituted Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives As Potent, Cell Permeable, KDM4 (JMJD2) and KDM5 (JARID1) Histone Lysine Demethylase Inhibitors. — J Med Chem

Cellosaurus cell lines

10 cell lines: 7 cancer cell line, 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A3M5	SEES3-1V human KDM5B, clone1	Embryonic stem cell	Male
CVCL_A3M6	SEES3-1V human KDM5B, clone2	Embryonic stem cell	Male
CVCL_A3M7	SEES3-1V human KDM5B, clone3	Embryonic stem cell	Male
CVCL_B8J6	Abcam HCT 116 KDM5B KO	Cancer cell line	Male
CVCL_B8Y0	Abcam MCF-7 KDM5B KO	Cancer cell line	Female
CVCL_B9LH	Abcam A-549 KDM5B KO	Cancer cell line	Male
CVCL_F1SS	HyCyte PANC-1 KO-hKDM5B	Cancer cell line	Male
CVCL_SU42	HAP1 KDM5B (-) 1	Cancer cell line	Male
CVCL_SU43	HAP1 KDM5B (-) 2	Cancer cell line	Male
CVCL_SU44	HAP1 KDM5B (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00152750	PHASE4	UNKNOWN	Study of Clonidine on Sleep Architecture in Children With Tourette’s Syndrome (TS) and Comorbid ADHD
NCT00226824	PHASE4	TERMINATED	Safety Study of Galantamine in Tic Disorders
NCT00241176	PHASE4	COMPLETED	Open Label Trial of Aripiprazole in Children and Adolescents With Tourette’s Disorder
NCT00370838	PHASE4	COMPLETED	Comparison of Keppra and Clonidine in the Treatment of Tics
NCT01018056	PHASE4	COMPLETED	Developing New Treatments for Tourette Syndrome: Therapeutic Trials With Modulators of Glutamatergic Neurotransmission
NCT01547000	PHASE4	COMPLETED	Guanfacine in Children With Tic Disorders
NCT03239210	PHASE4	COMPLETED	Effects of Ondansetron in Obsessive-compulsive and Tic Disorders
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00004376	PHASE3	COMPLETED	Phase III Randomized, Double-Blind, Placebo-Controlled Study of Guanfacine for Tourette Syndrome and Attention Deficit Hyperactivity Disorder
NCT00206323	PHASE3	COMPLETED	A Randomized, Placebo-controlled, Tourette Syndrome Study.
NCT00206336	PHASE3	COMPLETED	An Open-label Study to Determine the Efficacy and Safety of Topiramate in the Treatment of Tourette Syndrome.
NCT00478842	PHASE3	COMPLETED	Pallidal Stimulation and Gilles de la Tourette Syndrome
NCT00681863	PHASE3	TERMINATED	Open-label Extension Study of Pramipexole in the Treatment of Children and Adolescents With Tourette Syndrome
NCT01501695	PHASE3	COMPLETED	Phase III Study of 5LGr to Treat Tic Disorder
NCT03087201	PHASE3	COMPLETED	CANNAbinoids in the Treatment of TICS (CANNA-TICS)
NCT03487783	PHASE3	COMPLETED	Aripiprazole Oral Solution in the Treatment of Children and Adolescents With Tourette’s Syndrome
NCT03567291	PHASE3	TERMINATED	Evaluation of Safety and Tolerability of Long-term TEV-50717 (Deutetrabenazine) for Treatment of Tourette Syndrome in Children and Adolescents
NCT03571256	PHASE3	COMPLETED	A Study to Test if TEV-50717 is Effective in Relieving Tics Associated With Tourette Syndrome (TS)
NCT06021522	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate Long-term Safety of Ecopipam Tablets in Children, Adolescents and Adults With Tourette’s Disorder
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00004393	PHASE2	COMPLETED	Phase II Double Blind Placebo Controlled Trial of Risperidone in Tourette Syndrome
NCT00004652	PHASE2	COMPLETED	Phase II Pilot Controlled Study of Short Vs Longer Term Pimozide (Orap) Therapy in Tourette Syndrome
NCT00231985	PHASE2	COMPLETED	Effectiveness of Behavior Therapy and Psychosocial Therapy for the Treatment of Tourette Syndrome and Chronic Tic Disorder
NCT00311909	PHASE2	COMPLETED	Thalamic Deep Brain Stimulation for Tourette Syndrome
NCT00529308	PHASE2	COMPLETED	Transcranial Magnetic Stimulation (TMS) for Individuals With Tourette’s Syndrome
NCT00558467	PHASE2	COMPLETED	Pramipexole Pilot Phase II Study in Children and Adolescents With Tourette Disorder According to DSM-IV Criteria
NCT01043549	PHASE2	TERMINATED	Repetitive Transcranial Magnetic Stimulation of the Posterior Parietal Cortex in Patients Suffering From Gilles de la Tourette Syndrome
NCT01133353	PHASE2	WITHDRAWN	A Study of the Effectiveness and Safety of Tetrabenazine MR in Pediatric Subjects With Tourette’s Syndrome
NCT01475383	PHASE2	WITHDRAWN	Study Evaluating The Safety And Efficacy Of PF-03654746 In Adult Subjects With Tourette’s Syndrome
NCT01647269	PHASE2	COMPLETED	A Trial of Bilateral Deep Brain Stimulation to the Globus Pallidus Internum in Tourette Syndrome
NCT01904773	PHASE2	COMPLETED	Safety, Tolerability, Pharmacokinetic, and Efficacy Study of AZD5213 in Adolescents With Tourette’s Disorder