SIK3

Summary

SIK3 (SIK family kinase 3, HGNC:29165) is a protein-coding gene on chromosome 11q23.3, encoding Serine/threonine-protein kinase SIK3 (Q9Y2K2). Positive regulator of mTOR signaling that functions by triggering the degradation of DEPTOR, an mTOR inhibitor.

Enables ATP binding activity; magnesium ion binding activity; and protein serine/threonine kinase activity. Involved in positive regulation of TORC1 signaling; positive regulation of TORC2 signaling; and protein phosphorylation. Predicted to be active in cytoplasm.

Source: NCBI Gene 23387 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spondyloepimetaphyseal dysplasia, Krakow type (Moderate, GenCC) — +2 more curated relationships
• GWAS associations: 34
• Clinical variants (ClinVar): 180 total — 2 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 39
• Druggable target: yes — 25 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001366686

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29165
Approved symbol	SIK3
Name	SIK family kinase 3
Location	11q23.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ12240, L19, KIAA0999, QSK
Ensembl gene	ENSG00000160584
Ensembl biotype	protein_coding
OMIM	614776
Entrez	23387

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 22 protein_coding, 4 retained_intron, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000375300, ENST00000413553, ENST00000415541, ENST00000445177, ENST00000446921, ENST00000454905, ENST00000465421, ENST00000472648, ENST00000480222, ENST00000480468, ENST00000485363, ENST00000488337, ENST00000497049, ENST00000878032, ENST00000878033, ENST00000923910, ENST00000923911, ENST00000923912, ENST00000923913, ENST00000923914, ENST00000923915, ENST00000923916, ENST00000923917, ENST00000923918, ENST00000954062, ENST00000954063, ENST00000954064, ENST00000954065, ENST00000954066, ENST00000954067

RefSeq mRNA: 5 — MANE Select: NM_001366686 NM_001281748, NM_001281749, NM_001366686, NM_001366687, NM_025164

CCDS: CCDS60974, CCDS8379, CCDS91600

Canonical transcript exons

ENST00000445177 — 25 exons

Exon	Start	End
ENSE00001053083	116857810	116858699
ENSE00001466645	116843402	116845629
ENSE00001466675	117098143	117098428
ENSE00001683204	116867946	116868089
ENSE00003459760	116873481	116873636
ENSE00003469721	116875374	116875451
ENSE00003477813	116863668	116863818
ENSE00003478604	116847476	116847608
ENSE00003485377	116846383	116846553
ENSE00003492000	116927219	116927380
ENSE00003496088	116870331	116870401
ENSE00003510258	116849120	116849283
ENSE00003535587	116896253	116896376
ENSE00003540199	116859265	116859604
ENSE00003542394	116862202	116862327
ENSE00003547637	116956948	116957064
ENSE00003580324	116861841	116861926
ENSE00003622629	116861274	116861383
ENSE00003629324	116954044	116954107
ENSE00003638218	116897193	116897317
ENSE00003640271	116875866	116876009
ENSE00003672900	116875158	116875267
ENSE00003681421	116876924	116877042
ENSE00003691349	116873903	116874056
ENSE00003694073	116876253	116876363

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 98.81.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 39.2289 / max 1086.2939, expressed in 1819 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
122469	38.5294	1819
122470	0.6995	355

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral globus pallidus	UBERON:0002476	98.81	gold quality
corpus callosum	UBERON:0002336	98.54	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.50	gold quality
substantia nigra pars reticulata	UBERON:0001966	98.17	gold quality
sperm	CL:0000019	98.15	gold quality
substantia nigra pars compacta	UBERON:0001965	97.92	gold quality
inferior vagus X ganglion	UBERON:0005363	97.47	gold quality
ventral tegmental area	UBERON:0002691	97.38	gold quality
male germ cell	CL:0000015	97.33	gold quality
middle frontal gyrus	UBERON:0002702	97.29	gold quality
subthalamic nucleus	UBERON:0001906	97.28	gold quality
dorsal plus ventral thalamus	UBERON:0001897	97.00	gold quality
endothelial cell	CL:0000115	96.74	gold quality
CA1 field of hippocampus	UBERON:0003881	96.47	gold quality
pons	UBERON:0000988	96.27	gold quality
cerebellar vermis	UBERON:0004720	96.10	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.06	gold quality
superior vestibular nucleus	UBERON:0007227	95.96	gold quality
globus pallidus	UBERON:0001875	95.76	gold quality
medulla oblongata	UBERON:0001896	95.74	gold quality
occipital lobe	UBERON:0002021	95.63	gold quality
putamen	UBERON:0001874	95.50	gold quality
primary visual cortex	UBERON:0002436	95.37	gold quality
sural nerve	UBERON:0015488	95.28	gold quality
medial globus pallidus	UBERON:0002477	95.13	gold quality
caudate nucleus	UBERON:0001873	95.10	gold quality
middle temporal gyrus	UBERON:0002771	94.86	gold quality
adult organism	UBERON:0007023	94.79	gold quality
inferior olivary complex	UBERON:0002127	94.58	gold quality
Brodmann (1909) area 10	UBERON:0013541	94.52	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	3326.81
E-HCAD-25	yes	3291.89
E-ANND-3	yes	6.73

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

96 targeting SIK3, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753

Literature-anchored findings (GeneRIF, showing 21)

• Fecal ribosomal protein L19 is a genetic prognostic factor for survival in colorectal cancer. (PMID:18266979)
• Overexpression of SIK3 promotes G1/S cell cycle progression, bestows survival advantages to cancer cells for growth and correlates the clinicopathological conditions of patients with ovarian cancer. (PMID:21399663)
• cAMP-mediated regulation of SIK3 suggest that SIK3 may mediate some of the effects of this important second messenger in adipocytes (PMID:22588126)
• tumor suppressor kinase LKB1 activates the downstream kinases SIK2 and SIK3 to stimulate nuclear export of class IIa histone deacetylases (PMID:23393134)
• These results establish the importance of SIK3 as a mitotic regulator and underscore the potential of SIK3 as a druggable antimitotic target. (PMID:24743732)
• SIK3 variants were associated with hypertriglyceridemia in Mexicans. (PMID:24886709)
• Developmental role of Sik3 in hearing and requirement for the maintenance of adult auditory function is reported. (PMID:25060954)
• salt-inducible kinase inhibition decreases proinflammatory cytokines in human myeloid cells upon IL-1R stimulation. (PMID:26590148)
• SIK3 is activated in human osteoarthritic cartilage. (PMID:27009967)
• Data demonstrate that SIK2 and SIK3 mRNA are downregulated in adipose tissue from obese individuals and that the expression is regulated by weight change. SIK2 is also negatively associated with in vivo insulin resistance (HOMA-IR), independently of BMI and age. (PMID:27807598)
• Results found that CpG sites of C1orf106, DMBX1, and SIK3 mediate the genetic risk of psoriasis in Chinese Han population. (PMID:27980695)
• role in mediating high salt and IL-17 synergy leading to breast cancer cell proliferation (PMID:28658303)
• Data suggest that cAMP/protein kinase A-dependent phosphorylation of SIK1, SIK2, and SIK3 inhibits their catalytic activity by inducing 14-3-3 protein binding. (PMID:29211348)
• Targeting of LKB1 or SIK3 diminishes histone acetylation at MEF2C-bound enhancers and deprives leukemia cells of the output of this essential TF. (PMID:29526696)
• An LKB1-SIK Axis Suppresses Lung Tumor Growth and Controls Differentiation. (PMID:31350327)
• High-Throughput Implementation of the NanoBRET Target Engagement Intracellular Kinase Assay to Reveal Differential Compound Engagement by SIK2/3 Isoforms. (PMID:31849250)
• Salt-inducible kinases (SIKs) regulate TGFbeta-mediated transcriptional and apoptotic responses. (PMID:31969556)
• Salt-Inducible Kinase 3 Haplotypes Associated with Noise-Induced Hearing Loss in Chinese Workers. (PMID:32126566)
• Salt-inducible Kinases Are Critical Determinants of Female Fertility. (PMID:32343771)
• [Analysis of SIK3 gene variation in a boy with autism spectrum disorder complicated with epilepsy]. (PMID:34839513)
• Targeting SIK3 to modulate hippocampal synaptic plasticity and cognitive function by regulating the transcription of HDAC4 in a mouse model of Alzheimer’s disease. (PMID:38057370)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	sik3	ENSDARG00000088083
mus_musculus	Sik3	ENSMUSG00000034135
rattus_norvegicus	Sik3	ENSRNOG00000045931
caenorhabditis_elegans		WBGENE00012638
caenorhabditis_elegans	tag-344	WBGENE00015230
caenorhabditis_elegans		WBGENE00044388

Paralogs (17): NUAK1 (ENSG00000074590), PRKAA1 (ENSG00000132356), TSSK4 (ENSG00000139908), HUNK (ENSG00000142149), SIK1 (ENSG00000142178), BRSK1 (ENSG00000160469), PRKAA2 (ENSG00000162409), TSSK3 (ENSG00000162526), NUAK2 (ENSG00000163545), SNRK (ENSG00000163788), MELK (ENSG00000165304), SIK2 (ENSG00000170145), BRSK2 (ENSG00000174672), NIM1K (ENSG00000177453), TSSK6 (ENSG00000178093), TSSK2 (ENSG00000206203), TSSK1B (ENSG00000212122)

Protein

Protein identifiers

Serine/threonine-protein kinase SIK3 — Q9Y2K2 (reviewed: Q9Y2K2)

Alternative names: Salt-inducible kinase 3, Serine/threonine-protein kinase QSK

All UniProt accessions (5): Q9Y2K2, H0Y4E8, H7C038, H7C042, H7C3X8

UniProt curated annotations — full annotation on UniProt →

Function. Positive regulator of mTOR signaling that functions by triggering the degradation of DEPTOR, an mTOR inhibitor. Involved in the dynamic regulation of mTOR signaling in chondrocyte differentiation during skeletogenesis. Negatively regulates cAMP signaling pathway possibly by acting on CRTC2/TORC2 and CRTC3/TORC3. Prevents HDAC4 translocation to the nucleus.

Subunit / interactions. Binds to and is activated by YWHAZ when phosphorylated on Thr-221. Interacts with 14-3-3 proteins. Interacts with HDAC4; this interaction leads to HDAC4 retention in the cytoplasm. Interacts with DEPTOR, MLST8/GbetaL, RICTOR and RPTOR.

Subcellular location. Cytoplasm.

Tissue specificity. Expressed in chondrocytes.

Post-translational modifications. Phosphorylated at Thr-221 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39. Phosphorylation at Thr-221 is inhibited in response to PTHLH/PTHrP. Phosphorylated at Thr-469 and Ser-551 in response to cAMP signaling.

Disease relevance. Spondyloepimetaphyseal dysplasia, Krakow type (SEMDK) [MIM:618162] An autosomal recessive skeletal disorder characterized by severe spondyloepimetaphyseal dysplasia, rhizomelia, mesomelia with significant anterior bowing of all limbs, severe immunodeficiency, and developmental delay. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by phosphorylation on Thr-221.

Similarity. Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. SNF1 subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9Y2K2-5	1	yes
Q9Y2K2-6	2
Q9Y2K2-7	3
Q9Y2K2-8	4

RefSeq proteins (4): NP_001268677, NP_001268678, NP_001353615, NP_079440 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR015940	UBA	Domain
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR034672	SIK	Domain
IPR057380	UBA_SIK1/2/3	Domain

Pfam: PF00069, PF23312

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (75 total): helix 15, modified residue 12, compositionally biased region 8, strand 8, mutagenesis site 7, splice variant 6, region of interest 5, sequence variant 5, turn 3, domain 2, binding site 2, chain 1, active site 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
8R4V	X-RAY DIFFRACTION	1.9
8R4U	X-RAY DIFFRACTION	2.42
8R4O	X-RAY DIFFRACTION	2.73
8R4Q	X-RAY DIFFRACTION	2.84
8OKU	X-RAY DIFFRACTION	3.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y2K2-F1	51.61	0.22

Antibody-complex structures (SAbDab): 3 — 8R4O, 8R4Q, 8R4U

Functional residue map

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

Catalytic / active sites (1): 188 (proton acceptor)

Ligand- & substrate-binding residues (2): 72–80; 95

Post-translational modifications (12): 71, 221, 469, 551, 591, 592, 626, 647, 866, 978, 986, 113

Mutagenesis-validated functional residues (7):

Position	Phenotype
221	prevents phosphorylation and activation by stk11/lkb1 complex.
469	loss of interaction with 14-3-3 proteins in response to camp signaling; inhibits camp signaling.
551	loss of interaction with 14-3-3 proteins in response to camp signaling; inhibits camp signaling.
626	no effect on interaction with 14-3-3 proteins, nor on camp signaling.
626	no effect on camp signaling.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 370 (showing top): MORF_RAGE, RNGTGGGC_UNKNOWN, GCM_MAP4K4, GCM_PTPRD, NKX25_02, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, MORF_ATRX, GOBP_POSITIVE_REGULATION_OF_TOR_SIGNALING, TGACCTY_ERR1_Q2, MEF2_02, HASLINGER_B_CLL_WITH_11Q23_DELETION, TTGCWCAAY_CEBPB_02, SREBP1_02, OSWALD_HEMATOPOIETIC_STEM_CELL_IN_COLLAGEN_GEL_UP, MORF_FANCG

GO Biological Process (11): microtubule cytoskeleton organization (GO:0000226), protein phosphorylation (GO:0006468), intracellular signal transduction (GO:0035556), positive regulation of TORC1 signaling (GO:1904263), positive regulation of TORC2 signaling (GO:1904515), endochondral ossification (GO:0001958), regulation of protein localization (GO:0032880), limb morphogenesis (GO:0035108), multicellular organism growth (GO:0035264), skeletal system morphogenesis (GO:0048705), cartilage development involved in endochondral bone morphogenesis (GO:0060351)

GO Molecular Function (11): magnesium ion binding (GO:0000287), protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), tau-protein kinase activity (GO:0050321), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (1): cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular anatomical structure	2
positive regulation of TOR signaling	2
endochondral bone morphogenesis	2
protein kinase activity	2
cytoskeleton organization	1
microtubule-based process	1
phosphorylation	1
protein modification process	1
signal transduction	1
TORC1 signaling	1
regulation of TORC1 signaling	1
TORC2 signaling	1
regulation of TORC2 signaling	1
replacement ossification	1
intracellular protein localization	1
regulation of localization	1
appendage morphogenesis	1
limb development	1
multicellular organismal process	1
developmental growth	1
skeletal system development	1
animal organ morphogenesis	1
cartilage development	1
metal ion binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
protein serine/threonine kinase activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
cation binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1540 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SIK3	NUAK2	Q9H093	603
SIK3	CRTC3	Q6UUV7	588
SIK3	CRTC2	Q53ET0	567
SIK3	NALCN	Q8IZF0	533
SIK3	BUD13	Q9BRD0	515
SIK3	MAGI3	Q5TCQ9	507
SIK3	NUAK1	O60285	478
SIK3	HDAC4	P56524	475
SIK3	SIK2	Q9H0K1	473
SIK3	SIK1	P57059	458
SIK3	A0A0B4J2F2	A0A0B4J2F2	458
SIK3	APOA5	Q6Q788	453
SIK3	MARK1	Q9P0L2	449
SIK3	AURKB	Q96GD4	445
SIK3	SCGN	O76038	442

IntAct

68 interactions, top by confidence:

A	B	Type	Score
YWHAZ	MARK3	psi-mi:“MI:0914”(association)	0.940
PPP3CA	PPP3R1	psi-mi:“MI:0914”(association)	0.900
PPP3CA	PPP3R1	psi-mi:“MI:0914”(association)	0.830
SIK1	GINS4	psi-mi:“MI:0914”(association)	0.800
SIK3	YWHAZ	psi-mi:“MI:0407”(direct interaction)	0.760
YWHAZ	SIK3	psi-mi:“MI:0407”(direct interaction)	0.760
SIK3	YWHAE	psi-mi:“MI:0914”(association)	0.670
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
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
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
PPP3CC	NFATC1	psi-mi:“MI:0914”(association)	0.530
PPP3CC	GSK3A	psi-mi:“MI:0914”(association)	0.530
CRTC2	SIK3	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
SIK3	OCIAD2	psi-mi:“MI:0915”(physical association)	0.400
SIK3	TRIP6	psi-mi:“MI:0915”(physical association)	0.370
E6	TRAFD1	psi-mi:“MI:0914”(association)	0.350
HIF1AN	CNOT1	psi-mi:“MI:0914”(association)	0.350
EGLN3	FAM168B	psi-mi:“MI:0914”(association)	0.350
	PLK4	psi-mi:“MI:0914”(association)	0.350
	TBKBP1	psi-mi:“MI:0914”(association)	0.350
	AURKA	psi-mi:“MI:0914”(association)	0.350
MAPT	NCAN	psi-mi:“MI:0914”(association)	0.350
PPP3CC	NFATC1	psi-mi:“MI:0914”(association)	0.350

BioGRID (134): SIK3 (Two-hybrid), SIK3 (Two-hybrid), SIK3 (Affinity Capture-MS), SIK3 (Affinity Capture-MS), TRIP6 (Two-hybrid), SIK3 (Affinity Capture-MS), SIK3 (Affinity Capture-MS), SIK3 (Affinity Capture-MS), SIK3 (Affinity Capture-RNA), SIK3 (Affinity Capture-MS), SIK3 (Affinity Capture-MS), SIK3 (Affinity Capture-MS), SIK3 (Affinity Capture-RNA), SIK3 (Proximity Label-MS), SIK3 (Proximity Label-MS)

ESM2 similar proteins: A0A1W2PQ72, A4IFD2, A7MBH3, D3ZXW3, O35260, O35750, O57337, P14003, P15257, P20823, P22361, P35428, P39880, P42128, P53564, P53565, P56524, P81069, P83038, P85037, Q01167, Q01664, Q04666, Q0V8G2, Q14469, Q3UCQ1, Q3ZBG4, Q5R902, Q5ZI27, Q69YI7, Q6NSM8, Q6NZM9, Q6PFD7, Q6ZTZ1, Q7TSZ8, Q7ZX03, Q80ZH1, Q8BIL2, Q8TAK5, Q8UW00

Diamond homologs: A0AUV4, A1A5Q6, A2KF29, A2XFF4, A8WYE4, B2DD29, B7XHR6, B8BBT7, C0HKC8, C0HKC9, F1QGZ6, O08678, O08679, O22932, O22971, O65554, O74536, O94168, P27448, P52497, P54645, P54646, P57059, P92958, Q00372, Q02723, Q03141, Q05512, Q09137, Q0D4B2, Q0JI49, Q13131, Q19469, Q28948, Q2QY53, Q2RAX3, Q2V452, Q38997, Q54DF2, Q54TA3

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
STK11	up-regulates	SIK3	phosphorylation
SIK3	“down-regulates activity”	CRTC2	phosphorylation
SIK3	“down-regulates activity”	HDAC4	phosphorylation
SIK3	“down-regulates quantity by destabilization”	PER2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 63 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
Activation of BAD and translocation to mitochondria	9	145.8×	3e-16
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	100.0×	2e-11
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	100.0×	2e-11
Activation of BH3-only proteins	8	84.5×	3e-12
Intrinsic Pathway for Apoptosis	8	49.8×	2e-10
RHO GTPases activate PKNs	7	47.2×	4e-09
FOXO-mediated transcription	5	35.7×	5e-06
Apoptosis	9	32.2×	3e-10

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	32.1×	7e-05
intracellular protein localization	7	12.8×	1e-04
protein phosphorylation	6	7.2×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	112
Likely benign	22
Benign	9

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
2422186	NC_000011.9:g.(?116706880)(116714426_?)del	Pathogenic
587366	NM_001366686.3(SIK3):c.559C>T (p.Arg187Cys)	Pathogenic
3024353	NM_001366686.3(SIK3):c.950T>G (p.Met317Arg)	Likely pathogenic

SpliceAI

6296 predictions. Top by Δscore:

Variant	Effect	Δscore
11:116846027:T:TA	donor_gain	1.0000
11:116846382:CTCT:C	donor_gain	1.0000
11:116847474:AC:A	donor_gain	1.0000
11:116847475:CC:C	donor_gain	1.0000
11:116847490:T:TA	donor_gain	1.0000
11:116847525:A:AC	donor_gain	1.0000
11:116847526:C:CC	donor_gain	1.0000
11:116849059:CT:C	donor_gain	1.0000
11:116849118:A:AC	donor_gain	1.0000
11:116849119:C:CC	donor_gain	1.0000
11:116862198:CTA:C	donor_loss	1.0000
11:116862199:TA:T	donor_loss	1.0000
11:116862200:A:AC	donor_gain	1.0000
11:116862200:ACTT:A	donor_loss	1.0000
11:116862201:C:CA	donor_loss	1.0000
11:116862201:C:CC	donor_gain	1.0000
11:116862323:CACTC:C	acceptor_gain	1.0000
11:116862325:CTC:C	acceptor_gain	1.0000
11:116862329:T:C	acceptor_loss	1.0000
11:116863664:TTA:T	donor_loss	1.0000
11:116863665:TA:T	donor_loss	1.0000
11:116863666:A:AG	donor_loss	1.0000
11:116863667:CCT:C	donor_loss	1.0000
11:116870398:CTGC:C	acceptor_gain	1.0000
11:116870402:CT:C	acceptor_loss	1.0000
11:116873475:ACT:A	donor_loss	1.0000
11:116873476:CTC:C	donor_loss	1.0000
11:116873477:TCA:T	donor_loss	1.0000
11:116873478:CACTG:C	donor_loss	1.0000
11:116873479:A:AC	donor_gain	1.0000

AlphaMissense

9040 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:116873563:T:A	D552V	1.000
11:116873564:C:G	D552H	1.000
11:116876960:C:A	W316C	1.000
11:116876960:C:G	W316C	1.000
11:116876961:C:G	W316S	1.000
11:116876962:A:G	W316R	1.000
11:116876962:A:T	W316R	1.000
11:116876995:G:T	R305S	1.000
11:116877015:A:C	L298W	1.000
11:116877015:A:G	L298S	1.000
11:116877024:C:G	R295P	1.000
11:116877027:A:T	I294N	1.000
11:116877038:A:C	C290W	1.000
11:116877039:C:T	C290Y	1.000
11:116877040:A:G	C290R	1.000
11:116896263:A:C	F285L	1.000
11:116896263:A:T	F285L	1.000
11:116896264:A:C	F285C	1.000
11:116896264:A:G	F285S	1.000
11:116896265:A:G	F285L	1.000
11:116896265:A:T	F285I	1.000
11:116896266:A:C	F284L	1.000
11:116896266:A:T	F284L	1.000
11:116896268:A:G	F284L	1.000
11:116896270:G:C	P283R	1.000
11:116896270:G:T	P283Q	1.000
11:116896271:G:T	P283T	1.000
11:116896273:A:T	I282N	1.000
11:116896278:G:C	F280L	1.000
11:116896278:G:T	F280L	1.000

dbSNP variants (sampled 300 via entrez): RS1000002222 (11:117005378 A>C,G), RS1000012303 (11:116920631 G>A,C), RS1000024841 (11:116969191 G>A,T), RS1000027050 (11:117012089 C>T), RS1000047666 (11:116876501 G>A,C), RS1000052573 (11:116964534 G>A), RS1000070857 (11:117053187 A>C,G), RS1000078840 (11:116926189 T>C), RS1000081402 (11:116978833 T>C), RS1000104800 (11:116884170 T>C), RS1000118180 (11:117012336 T>C), RS1000137504 (11:116883878 G>A), RS1000154178 (11:116970278 T>C), RS1000169252 (11:117017708 C>T), RS1000188113 (11:117059450 T>C,G)

Disease associations

OMIM: gene MIM:614776 | disease phenotypes: MIM:618162

GenCC curated gene-disease

Disease	Classification	Inheritance
spondyloepimetaphyseal dysplasia, Krakow type	Moderate	Autosomal recessive
autism	Limited	Autosomal dominant
hearing loss disorder	Limited	Autosomal dominant

Mondo (3): spondyloepimetaphyseal dysplasia, Krakow type (MONDO:0032571), autism (MONDO:0005260), hearing loss disorder (MONDO:0005365)

Orphanet (0):

HPO phenotypes

39 total (30 of 39 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000316	Hypertelorism
HP:0000750	Delayed speech and language development
HP:0000767	Pectus excavatum
HP:0000964	Eczematoid dermatitis
HP:0000978	Bruising susceptibility
HP:0001156	Brachydactyly
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001631	Atrial septal defect
HP:0001643	Patent ductus arteriosus
HP:0001734	Annular pancreas
HP:0002007	Frontal bossing
HP:0002019	Constipation
HP:0002099	Asthma
HP:0002308	Chiari malformation
HP:0002691	Platybasia
HP:0002694	Sclerosis of skull base
HP:0002721	Immunodeficiency
HP:0002850	Decreased circulating total IgM
HP:0003025	Metaphyseal irregularity
HP:0003027	Mesomelia
HP:0003049	Ulnar deviation of the wrist
HP:0003155	Elevated circulating alkaline phosphatase concentration
HP:0003193	Allergic rhinitis
HP:0003577	Congenital onset
HP:0004209	Clinodactyly of the 5th finger
HP:0004691	2-3 toe syndactyly

GWAS associations

34 associations (top):

Study	Trait	p-value
GCST000137_2	Triglycerides	5.000000e-08
GCST001450_3	Response to Vitamin E supplementation	3.000000e-12
GCST001523_37	Visceral adipose tissue adjusted for BMI	5.000000e-06
GCST001905_3	Hypertriglyceridemia	5.000000e-35
GCST002468_3	Triglycerides	7.000000e-09
GCST002469_1	HDL cholesterol	3.000000e-10
GCST002543_3	Hearing function	4.000000e-08
GCST003364_2	Triglyceride levels	1.000000e-30
GCST004600_2	Eosinophil percentage of white cells	1.000000e-09
GCST004606_198	Eosinophil count	1.000000e-11
GCST004624_183	Sum eosinophil basophil counts	2.000000e-09
GCST005780_10	Triglyceride levels	7.000000e-19
GCST005851_19	Delirium	3.000000e-06
GCST006409_18	Allergic rhinitis	7.000000e-07
GCST007738_20	Metabolic syndrome	3.000000e-11
GCST007738_21	Metabolic syndrome	1.000000e-11
GCST007738_22	Metabolic syndrome	6.000000e-10
GCST007932_91	Medication use (thyroid preparations)	2.000000e-09
GCST008141_1	HDL cholesterol	4.000000e-08
GCST008741_4	Non-accommodative esotropia	6.000000e-06
GCST009889_1	Body mass index	5.000000e-08
GCST010002_199	Refractive error	3.000000e-34
GCST010060_12	Cholesterol	9.000000e-14
GCST010242_474	HDL cholesterol levels	2.000000e-36
GCST010242_502	HDL cholesterol levels	5.000000e-89
GCST010243_110	Apolipoprotein B levels	3.000000e-12
GCST010244_440	Triglyceride levels	2.000000e-09
GCST011925_3	Triglyceride levels x fish oil supplementation interaction (2df)	2.000000e-09
GCST011927_3	HDL levels x fish oil supplementation interaction (2df)	1.000000e-16
GCST90002381_523	Eosinophil count	6.000000e-18

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0004340	body mass index
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004842	eosinophil count
EFO:0005090	basophil count
EFO:0000195	metabolic syndrome
EFO:0009933	Thyroid preparation use measurement
EFO:0004615	apolipoprotein B measurement
EFO:0600007	fish oil supplement exposure measurement
EFO:0004309	platelet count
EFO:0009188	Red cell distribution width

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6149 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

25 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 119,868 (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
CHEMBL1078178	MOMELOTINIB	4	3,481
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL2028663	DABRAFENIB	4	12,430
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL5416410	DASATINIB	4	655
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL2105728	CRENOLANIB	3	2,167
CHEMBL217092	SARACATINIB	3	3,982
CHEMBL31965	CANERTINIB	3	8,083
CHEMBL603469	LESTAURTINIB	3
CHEMBL1944698	ZOTIRACICLIB	2	2,915
CHEMBL1950289	TANZISERTIB	2	419
CHEMBL253969	OSI-632	2	1,150
CHEMBL411907	SONOLISIB	2	2,705
CHEMBL495727	AT-9283	2	1,376
CHEMBL564829	MILCICLIB	2	821
CHEMBL574737	UCN-01	2	2,217
CHEMBL1908397	KW-2449	1	622
CHEMBL2041933	AZD-7762	1
CHEMBL3545328	XL-019	1
CHEMBL4289017	PF-03814735	1
CHEMBL482967	CYC-116	1
CHEMBL571948	Y-39983	1

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

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs533556	SIK3		0.00	0
rs139961185	SIK3		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — QIK subfamily

Most potent curated ligand interactions (7 total), top 7:

Ligand	Action	Affinity	Parameter
GLPG3970	Inhibition	11.0	pIC50
GLPG3312	Inhibition	9.22	pIC50
PF-07899895	Inhibition	8.74	pIC50
ARN-3236	Inhibition	8.18	pIC50
HG-9-91-01	Inhibition	8.02	pIC50
dasatinib	Inhibition	8.0	pIC50
bosutinib	Inhibition	7.74	pIC50

ChEMBL bioactivities

188 potent at pChembl≥5 of 200 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.51	IC50	0.031	nM	CHEMBL6148877
10.38	IC50	0.042	nM	CHEMBL6159758
9.39	IC50	0.41	nM	CHEMBL6160074
9.34	Kd	0.46	nM	STAUROSPORINE
9.22	IC50	0.6	nM	CHEMBL5417444
9.22	IC50	0.6	nM	CHEMBL5440720
9.13	IC50	0.74	nM	STAUROSPORINE
9.01	IC50	0.972	nM	STAUROSPORINE
9.00	IC50	1	nM	CHEMBL5438171
9.00	IC50	1	nM	CHEMBL5431938
9.00	IC50	1	nM	CHEMBL6146175
8.96	IC50	1.1	nM	CHEMBL5415380
8.96	IC50	1.1	nM	CHEMBL6162015
8.92	IC50	1.2	nM	CHEMBL5407103
8.91	IC50	1.24	nM	STAUROSPORINE
8.89	IC50	1.3	nM	CHEMBL5412961
8.85	IC50	1.4	nM	CHEMBL5404502
8.85	IC50	1.4	nM	CHEMBL5402124
8.77	IC50	1.7	nM	CHEMBL5439455
8.77	IC50	1.7	nM	CHEMBL5405883
8.77	IC50	1.7	nM	CHEMBL5437300
8.72	IC50	1.9	nM	CHEMBL5410472
8.70	Kd	2	nM	CRENOLANIB
8.66	IC50	2.2	nM	CHEMBL5397288
8.54	IC50	2.9	nM	CHEMBL5401167
8.52	Kd	3	nM	CHEMBL400402
8.51	IC50	3.1	nM	CHEMBL5419090
8.49	IC50	3.2	nM	CHEMBL5440381
8.44	IC50	3.6	nM	CHEMBL5410039
8.43	IC50	3.7	nM	CHEMBL5427025
8.42	IC50	3.8	nM	CHEMBL5393771
8.40	IC50	4	nM	CHEMBL5402213
8.40	IC50	4	nM	CHEMBL5430450
8.38	IC50	4.2	nM	CHEMBL5420455
8.38	IC50	4.2	nM	CHEMBL5430610
8.38	IC50	4.2	nM	CHEMBL5396179
8.36	IC50	4.4	nM	CHEMBL5410109
8.36	IC50	4.4	nM	CHEMBL5403558
8.35	IC50	4.5	nM	CHEMBL6172249
8.33	IC50	4.7	nM	CHEMBL5426058
8.30	IC50	5	nM	DASATINIB
8.30	IC50	5	nM	CHEMBL5415699
8.26	IC50	5.5	nM	CHEMBL6172811
8.24	IC50	5.7	nM	CHEMBL6164789
8.23	IC50	5.9	nM	CHEMBL5394880
8.22	IC50	6	nM	CHEMBL5090394
8.22	IC50	6	nM	CHEMBL4539742
8.22	IC50	6	nM	CHEMBL5424512
8.19	IC50	6.4	nM	CHEMBL5426204
8.18	IC50	6.6	nM	CHEMBL5398906

PubChem BioAssay actives

146 with measured affinity, of 588 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
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	624774: Binding constant for QSK kinase domain	kd	0.0005	uM
N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-(oxan-4-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide	1985484: Inhibition of full length SIK3 (unknown origin) using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0006	uM
N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide	1985484: Inhibition of full length SIK3 (unknown origin) using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0006	uM
2-(difluoromethoxy)-N-ethyl-4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-6-methoxybenzamide	1992750: Inhibition of human SIK3 isoform 1 (59 to 1321 residues) expressed in Sf9 insect cells using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo assay	ic50	0.0010	uM
4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxybenzamide	1992750: Inhibition of human SIK3 isoform 1 (59 to 1321 residues) expressed in Sf9 insect cells using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo assay	ic50	0.0010	uM
2-(difluoromethoxy)-N-ethyl-6-methoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide	1992750: Inhibition of human SIK3 isoform 1 (59 to 1321 residues) expressed in Sf9 insect cells using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo assay	ic50	0.0011	uM
2-[2,6-dimethoxy-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]phenyl]-5-ethyl-1,3,4-oxadiazole	1985481: Inhibition of SIK3 (unknown origin)	ic50	0.0012	uM
N-cyclopropyl-4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxybenzamide	1992750: Inhibition of human SIK3 isoform 1 (59 to 1321 residues) expressed in Sf9 insect cells using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo assay	ic50	0.0013	uM
4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide	1985484: Inhibition of full length SIK3 (unknown origin) using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0014	uM
4-[7-(4-acetylpiperazin-1-yl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide	1985484: Inhibition of full length SIK3 (unknown origin) using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0014	uM
N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(2-morpholin-4-ylethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide	1985484: Inhibition of full length SIK3 (unknown origin) using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0017	uM
N-cyclopropyl-2-(difluoromethoxy)-4-[7-[4-(dimethylamino)piperidin-1-yl]imidazo[1,2-a]pyridin-3-yl]-6-methoxybenzamide	1985484: Inhibition of full length SIK3 (unknown origin) using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0017	uM
N-cyclopropyl-4-[7-(3,3-difluoroazetidin-1-yl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxybenzamide	1985484: Inhibition of full length SIK3 (unknown origin) using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0017	uM
N-cyclopropyl-2-(difluoromethoxy)-4-[7-[4-(2-hydroxyethyl)piperazin-1-yl]imidazo[1,2-a]pyridin-3-yl]-6-methoxybenzamide	1985484: Inhibition of full length SIK3 (unknown origin) using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0019	uM
1-[2-[5-[(3-methyloxetan-3-yl)methoxy]benzimidazol-1-yl]quinolin-8-yl]piperidin-4-amine	1425167: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0020	uM
4-[5-[1-(cyanomethyl)pyrazol-4-yl]benzimidazol-1-yl]-N-ethyl-2,6-dimethoxybenzamide	1992750: Inhibition of human SIK3 isoform 1 (59 to 1321 residues) expressed in Sf9 insect cells using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo assay	ic50	0.0022	uM
N-ethyl-4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxybenzamide	1992750: Inhibition of human SIK3 isoform 1 (59 to 1321 residues) expressed in Sf9 insect cells using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo assay	ic50	0.0029	uM
4-chloro-3-[5-methyl-3-[4-(2-pyrrolidin-1-ylethoxy)anilino]-1,2,4-benzotriazin-7-yl]phenol	1425167: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0030	uM
N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-3-yl]benzamide	1985484: Inhibition of full length SIK3 (unknown origin) using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0031	uM
4-[7-(3,3-difluoroazetidin-1-yl)imidazo[1,2-a]pyridin-3-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide	1985484: Inhibition of full length SIK3 (unknown origin) using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0032	uM
N-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxyphenyl]imidazo[1,2-a]pyridin-7-yl]oxane-4-carboxamide	1985484: Inhibition of full length SIK3 (unknown origin) using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0036	uM
[4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxyphenyl]methanol	1992750: Inhibition of human SIK3 isoform 1 (59 to 1321 residues) expressed in Sf9 insect cells using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo assay	ic50	0.0037	uM
8-methoxy-6-[7-(2-morpholin-4-ylethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one	1985484: Inhibition of full length SIK3 (unknown origin) using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0038	uM
8-(4-aminobutyl)-6-[2,5-difluoro-4-(6-methyl-2-pyridinyl)phenyl]-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one	1974603: Inhibition of full length NanoLuc fused SIK3 (unknown origin) transfected in HEK293T cells using NanoBRET NanoGlo substrate incubated for 2 hrs in presence of tracer by NanoBRET assay	ic50	0.0040	uM
2-[8-methoxy-6-[2-[[2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]amino]-1,3-thiazol-5-yl]-1-oxo-3,4-dihydroisoquinolin-2-yl]acetonitrile	1975696: Inhibition of SIK3 (unknown origin) using AMARA as substrate buffer incubated for 60 mins followed by addition of ADP-Glo reagent further incubated for 60 mins	ic50	0.0040	uM
N-ethyl-4-[5-[1-(2-hydroxyethyl)pyrazol-4-yl]benzimidazol-1-yl]-2,6-dimethoxybenzamide	1985484: Inhibition of full length SIK3 (unknown origin) using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0042	uM
N-ethyl-2,6-dimethoxy-4-[5-[1-(oxan-4-yl)pyrazol-4-yl]benzimidazol-1-yl]benzamide	1992750: Inhibition of human SIK3 isoform 1 (59 to 1321 residues) expressed in Sf9 insect cells using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo assay	ic50	0.0042	uM
N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(2-morpholin-4-ylethylamino)imidazo[1,2-a]pyridin-3-yl]benzamide	1985484: Inhibition of full length SIK3 (unknown origin) using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0042	uM
N-ethyl-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide	1992750: Inhibition of human SIK3 isoform 1 (59 to 1321 residues) expressed in Sf9 insect cells using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo assay	ic50	0.0044	uM
N-cyclopropyl-2-(difluoromethoxy)-4-[7-[3-(dimethylamino)azetidin-1-yl]imidazo[1,2-a]pyridin-3-yl]-6-methoxybenzamide	1985484: Inhibition of full length SIK3 (unknown origin) using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0044	uM
2,6-dimethoxy-4-(7-morpholin-4-ylimidazo[1,2-a]pyridin-3-yl)-N-(2,2,2-trifluoroethyl)benzamide	1985484: Inhibition of full length SIK3 (unknown origin) using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0047	uM
4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxy-N-methylbenzamide	1992750: Inhibition of human SIK3 isoform 1 (59 to 1321 residues) expressed in Sf9 insect cells using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo assay	ic50	0.0050	uM
8-methoxy-6-[2-[[2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]amino]-1,3-thiazol-5-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one	1975696: Inhibition of SIK3 (unknown origin) using AMARA as substrate buffer incubated for 60 mins followed by addition of ADP-Glo reagent further incubated for 60 mins	ic50	0.0059	uM
N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-(7-morpholin-4-ylimidazo[1,2-a]pyridin-3-yl)benzamide	1985484: Inhibition of full length SIK3 (unknown origin) using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0060	uM
3-(2,4-dimethoxyphenyl)-4-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridine	1895090: Inhibition of SIK3 (unknown origin)	ic50	0.0060	uM
6-[2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-1,3-thiazol-5-yl]-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one	1975696: Inhibition of SIK3 (unknown origin) using AMARA as substrate buffer incubated for 60 mins followed by addition of ADP-Glo reagent further incubated for 60 mins	ic50	0.0064	uM
4-[5-[1-(2-amino-2-oxoethyl)pyrazol-4-yl]benzimidazol-1-yl]-N-ethyl-2,6-dimethoxybenzamide	1992750: Inhibition of human SIK3 isoform 1 (59 to 1321 residues) expressed in Sf9 insect cells using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo assay	ic50	0.0066	uM
3-(3,5-difluoro-2-methoxyphenyl)-5-(1-piperidin-4-ylpyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine	1985481: Inhibition of SIK3 (unknown origin)	ic50	0.0066	uM
N-ethyl-2,6-dimethoxy-4-[5-[1-(2-methoxyethyl)pyrazol-4-yl]benzimidazol-1-yl]benzamide	1992750: Inhibition of human SIK3 isoform 1 (59 to 1321 residues) expressed in Sf9 insect cells using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo assay	ic50	0.0068	uM
8-[(5-amino-1,3-dioxan-2-yl)methyl]-6-[2-chloro-4-(3-fluoro-2-pyridinyl)phenyl]-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one	1974603: Inhibition of full length NanoLuc fused SIK3 (unknown origin) transfected in HEK293T cells using NanoBRET NanoGlo substrate incubated for 2 hrs in presence of tracer by NanoBRET assay	ic50	0.0080	uM
8-methoxy-6-[2-[(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)amino]-1,3-thiazol-5-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one	1975696: Inhibition of SIK3 (unknown origin) using AMARA as substrate buffer incubated for 60 mins followed by addition of ADP-Glo reagent further incubated for 60 mins	ic50	0.0085	uM
1-(2,4-dimethoxyphenyl)-3-(2,6-dimethylphenyl)-1-[6-[4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]urea	1992913: Inhibition of GST fused recombinant SIK3 (unknown origin) expressed in HEK293 cells ALNRTSSDSALHRRR as substrate incubated for 1 hr in presence of ATP	ic50	0.0096	uM
N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-1,3-thiazole-5-carboxamide;hydrate	2017519: Inhibition of SIK3 (unknown origin)	ic50	0.0100	uM
3-(2,2-difluoro-10,12-dimethyl-1-aza-3-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-3,5,7,9,11-pentaen-4-yl)-N-[2-[2-[2-[2-[[(2S,3R,4R,6R)-3-methoxy-2-methyl-16-oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]propanamide	1526143: Binding affinity to recombinant N-terminal His-FLAG-GST-tagged SIK3 (unknown origin) (59 to 365 residues) expressed in baculovirus infected Sf9 insect cells incubated for 1 hr by TR-FRET assay	kd	0.0100	uM
methyl 4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxybenzoate	1992750: Inhibition of human SIK3 isoform 1 (59 to 1321 residues) expressed in Sf9 insect cells using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo assay	ic50	0.0102	uM
2,6-dimethoxy-4-[7-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)benzamide	1985484: Inhibition of full length SIK3 (unknown origin) using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0109	uM
[(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylidene]-5-hydroxy-9-(methoxymethyl)-9a,11a-dimethyl-1,4,7-trioxo-2,3,3a,9,10,11-hexahydroindeno[4,5-h]isochromen-10-yl] acetate	1425167: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0110	uM
N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(3-morpholin-4-ylanilino)imidazo[1,2-a]pyridin-3-yl]benzamide	1985484: Inhibition of full length SIK3 (unknown origin) using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0115	uM
2-cyclopropyl-8-methoxy-6-[7-(2-morpholin-4-ylethoxy)imidazo[1,2-a]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one	1985484: Inhibition of full length SIK3 (unknown origin) using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0117	uM
4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxybenzoic acid	1992750: Inhibition of human SIK3 isoform 1 (59 to 1321 residues) expressed in Sf9 insect cells using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo assay	ic50	0.0123	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases expression, affects cotreatment	3
Benzo(a)pyrene	affects methylation, increases expression	2
Cisplatin	decreases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
TAK-243	increases sumoylation	1
dicrotophos	increases expression	1
methylmercuric chloride	increases expression	1
bisphenol A	decreases methylation	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	increases methylation	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
PCI 5002	affects cotreatment, increases expression	1
Fulvestrant	increases methylation	1
Air Pollutants	affects expression, increases abundance	1
Arsenic	affects methylation	1
Carbamazepine	affects expression	1
Methapyrilene	increases methylation	1
Methotrexate	decreases expression	1
Methylcholanthrene	affects binding, increases reaction	1
Ozone	affects expression, increases abundance	1
Tobacco Smoke Pollution	increases expression	1
Zinc	affects cotreatment, increases expression	1
Asbestos, Crocidolite	increases expression	1
Antirheumatic Agents	decreases expression	1

ChEMBL screening assays

173 unique, capped per target: 173 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1043883	Binding	Binding affinity to QSK assessed as percentage of kinase remaining bound to the bead at 1 uM by T7 phage display based binding assay	Structure-based optimization of potent and selective inhibitors of the tyrosine kinase erythropoietin producing human hepatocellular carcinoma receptor B4 (EphB4). — J Med Chem

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_DX56	HAP1 SIK1 (-) SIK3 (-) 1	Cancer cell line	Male
CVCL_DX57	HAP1 SIK1 (-) SIK3 (-) 2	Cancer cell line	Male
CVCL_TL14	HAP1 SIK3 (-) 1	Cancer cell line	Male
CVCL_TL15	HAP1 SIK3 (-) 2	Cancer cell line	Male
CVCL_TL16	HAP1 SIK3 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT00036231	PHASE3	TERMINATED	Synthetic Human Secretin in Children With Autism and Gastrointestinal Dysfunction
NCT00036244	PHASE3	COMPLETED	Synthetic Human Secretin in Children With Autism
NCT00065884	PHASE3	UNKNOWN	Valproate Response in Aggressive Autistic Adolescents
NCT00065962	PHASE3	COMPLETED	Secretin for the Treatment of Autism
NCT00252603	PHASE3	COMPLETED	Galantamine Versus Placebo in Childhood Autism
NCT00346736	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00352248	PHASE3	COMPLETED	Randomized Controlled Trial of Acupuncture Versus Sham Acupuncture in Autistic Spectrum Disorder
NCT00352352	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00355329	PHASE3	COMPLETED	Randomized Control Trial of Using Tongue Acupuncture in Autistic Spectrum Disorder Using PET Scan for Clinical Correlation
NCT00498173	PHASE3	COMPLETED	Effectiveness of Atomoxetine in Treating ADHD Symptoms in Children and Adolescents With Autism
NCT00541346	PHASE3	COMPLETED	A Pilot Study of Daytrana TM in Children With Autism Co-Morbid for Attention Deficit Hyperactivity Disorder (ADHD) Symptoms