SIK1

Summary

SIK1 (salt inducible kinase 1, HGNC:11142) is a protein-coding gene on chromosome 21q22.3, encoding Serine/threonine-protein kinase SIK1 (P57059). Serine/threonine-protein kinase involved in various processes such as cell cycle regulation, gluconeogenesis and lipogenesis regulation, muscle growth and differentiation and tumor suppression.

This gene encodes a serine/threonine protein kinase that contains a ubiquitin-associated (UBA) domain. The encoded protein is a member of the adenosine monophosphate-activated kinase (AMPK) subfamily of kinases that play a role in conserved signal transduction pathways. A mutation in this gene is associated with early infantile epileptic encephalopathy 30.

Source: NCBI Gene 150094 — RefSeq curated summary.

At a glance

• Gene–disease (curated): developmental and epileptic encephalopathy, 30 (Definitive, GenCC) — +4 more curated relationships
• GWAS associations: 11
• Clinical variants (ClinVar): 1,115 total — 5 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 71
• Druggable target: yes — 19 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_173354

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11142
Approved symbol	SIK1
Name	salt inducible kinase 1
Location	21q22.3
Locus type	gene with protein product
Status	Approved
Aliases	msk
Ensembl gene	ENSG00000142178
Ensembl biotype	protein_coding
OMIM	605705
Entrez	150094

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 4 protein_coding, 4 retained_intron

ENST00000270162, ENST00000478426, ENST00000644276, ENST00000644689, ENST00000644750, ENST00000644871, ENST00000880889, ENST00000880890

RefSeq mRNA: 1 — MANE Select: NM_173354 NM_173354

CCDS: CCDS33575

Canonical transcript exons

ENST00000270162 — 14 exons

Exon	Start	End
ENSE00000952713	43426023	43426192
ENSE00000952714	43425407	43425523
ENSE00001050535	43419021	43419237
ENSE00001050539	43420234	43420457
ENSE00001050541	43418260	43418541
ENSE00001050542	43419353	43419478
ENSE00001050544	43417543	43417774
ENSE00001050545	43421010	43421133
ENSE00001050548	43419859	43420005
ENSE00001304380	43414483	43417117
ENSE00001319797	43421974	43422037
ENSE00001506914	43421638	43421799
ENSE00003564636	43421243	43421367
ENSE00003817113	43427010	43427131

Expression profiles

Bgee: expression breadth ubiquitous, 138 present calls, max score 97.49.

FANTOM5 (CAGE): breadth not_expressed, TPM avg 0.0005 / max 0.5056, expressed in 0 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
209216	2.0644	698
190699	0.0035	1
190698	0.0005	0

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of stomach	UBERON:0001199	97.49	gold quality
skin of abdomen	UBERON:0001416	97.01	gold quality
zone of skin	UBERON:0000014	95.95	gold quality
skin of leg	UBERON:0001511	95.35	gold quality
gall bladder	UBERON:0002110	95.24	gold quality
adrenal tissue	UBERON:0018303	93.57	gold quality
bone marrow cell	CL:0002092	93.05	gold quality
left ovary	UBERON:0002119	92.25	gold quality
left uterine tube	UBERON:0001303	92.03	gold quality
bone marrow	UBERON:0002371	92.03	gold quality
vagina	UBERON:0000996	91.51	gold quality
ovary	UBERON:0000992	91.40	gold quality
right ovary	UBERON:0002118	90.48	gold quality
omental fat pad	UBERON:0010414	90.41	gold quality
upper lobe of left lung	UBERON:0008952	90.29	gold quality
adipose tissue	UBERON:0001013	89.75	gold quality
subcutaneous adipose tissue	UBERON:0002190	89.36	gold quality
tibial nerve	UBERON:0001323	88.35	gold quality
smooth muscle tissue	UBERON:0001135	88.25	gold quality
lung	UBERON:0002048	88.13	gold quality
minor salivary gland	UBERON:0001830	87.22	gold quality
mammary gland	UBERON:0001911	86.26	gold quality
thoracic mammary gland	UBERON:0005200	86.26	gold quality
saliva-secreting gland	UBERON:0001044	86.15	gold quality
ectocervix	UBERON:0012249	85.83	gold quality
prostate gland	UBERON:0002367	85.73	gold quality
urinary bladder	UBERON:0001255	85.58	gold quality
tibial artery	UBERON:0007610	85.27	gold quality
popliteal artery	UBERON:0002250	85.14	gold quality
right atrium auricular region	UBERON:0006631	84.34	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-10287	yes	38.67
E-ENAD-27	yes	27.58
E-ANND-3	yes	13.89
E-CURD-46	yes	13.82

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1

miRNA regulators (miRDB)

144 targeting SIK1, 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-8485	100.00	77.57	4731
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482

Literature-anchored findings (GeneRIF, showing 30)

• the basic leucine zipper domain has a role in the regulation of transcriptional activity of CREB with TORC and salt inducible kinase [review] (PMID:17565599)
• part of a cell sodium-sensing network controlling active sodium transport (PMID:17939993)
• SIK is a negative regulator that controls TGFbeta receptor turnover and physiological signaling. (PMID:18725536)
• SIK1 links LKB1 to p53-dependent anoikis and suppresses metastasis. (PMID:19622832)
• activation of the RhoA-ROCK-p38MAPK-MSK signaling pathway is essential for the regulation of the phenotype and of the CST5/cystatin D candidate tumor suppressor and other target genes by 1,25(OH)2D3 in colon cancer cells (PMID:20223287)
• These results provide evidence that SIK1 is present in lung epithelial cells and that its function is relevant for the action of isoproterenol during regulation of active sodium transport. (PMID:21549091)
• We now demonstrate that TGFbeta induces SIK1 levels via a direct transcriptional mechanism that implicates the Smad proteins, and we have mapped a putative enhancer element on the SIK1 gene. (PMID:22378783)
• High SIK gene expression is assiciated with glioblastoma multiforme. (PMID:22395973)
• SIK1 is required for myogenic differentiation; it’s transcriptional regulation and regulated degradation comprise a unified molecular mechanism to precisely tune SIK1 activity in muscle cells. (PMID:23256157)
• These findings revealed a new function of LKB1 and salt-inducible kinases as negative regulators of HTLV-1 transcription. (PMID:23577667)
• Results show a role of SIK1 in gastrin induced responses and suggest that SIK1 may act as tumour suppressor in gastric adenocarcinoma cells. (PMID:25384047)
• De novo mutations in SIK1 cause a spectrum of developmental epilepsies. (PMID:25839329)
• salt-inducible kinase inhibition decreases proinflammatory cytokines in human myeloid cells upon IL-1R stimulation. (PMID:26590148)
• the results showed that miR-203 promotes proliferation, migration and invasion in pancreatic cancer cells, whereas the restoration of SIK1 abrogated the regulation of pre-miR203-mediated proliferation, migration and invasion. (PMID:26719072)
• Sld5 a component of GINS complex interacts with SIK1 and recruits it to the sites of DNA replication at the onset of S phase. (PMID:27592030)
• These data suggest that RNF2 is an important upstream negative regulator of SIK1 and that restoration of SIK1 levels induced by loss of RNF2 inhibited HCC cell growth and promoted apoptosis, which may represent a promising therapeutic strategy for HCC treatment. (PMID:27911266)
• SIK1 sequence variation was associated with abnormal neuronal morphology, abnormalities in the MEF2C-ARC pathway of neuronal development and synapse activity. (PMID:27966542)
• SIK1 plays a vital role in high glucose-induced lipid accumulation, and metformin suppresses lipogenesis via the induction and activation of SIK1. (PMID:28174122)
• 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)
• This work reveals a regulatory circuit in which SIK1 suppresses gluconeogenic gene transcription by inducing ubiquitination and degradation of CRTC1. (PMID:29408765)
• An LKB1-SIK Axis Suppresses Lung Tumor Growth and Controls Differentiation. (PMID:31350327)
• Sodium Channel Nav1.5 Controls Epithelial-to-Mesenchymal Transition and Invasiveness in Breast Cancer Cells Through its Regulation by the Salt-Inducible Kinase-1. (PMID:31819138)
• Exosomal miR-130b-3p targets SIK1 to inhibit medulloblastoma tumorigenesis. (PMID:32483145)
• SIK1 Regulates CRTC2-Mediated Gluconeogenesis Signaling Pathway in Human and Mouse Liver Cells. (PMID:33013689)
• Role of SIK1 in the transition of acute kidney injury into chronic kidney disease. (PMID:33588892)
• Exosomal microRNA-25 released from cancer cells targets SIK1 to promote hepatocellular carcinoma tumorigenesis. (PMID:34384713)
• Circ_0078607 inhibits the progression of ovarian cancer via regulating the miR-32-5p/SIK1 network. (PMID:34983607)
• Down-Regulation and Clinic-Pathological Correlation of SIK-1 and SIL-1-LNC in Non-Small Cell Lung Cancer Patients. (PMID:37116165)
• Integrated bioinformatics analyses identifying potential biomarkers for type 2 diabetes mellitus and breast cancer: In SIK1-ness and health. (PMID:37556419)
• Role of SIK1 in tumors: Emerging players and therapeutic potentials (Review). (PMID:39422046)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	sik1	ENSDARG00000058606
mus_musculus	Sik1	ENSMUSG00000024042
rattus_norvegicus	Sik1	ENSRNOG00000001189
drosophila_melanogaster	Snrk	FBGN0033915
drosophila_melanogaster	Nuak	FBGN0262617
caenorhabditis_elegans		WBGENE00012638
caenorhabditis_elegans	ZK524.4	WBGENE00013994
caenorhabditis_elegans	tag-344	WBGENE00015230
caenorhabditis_elegans		WBGENE00044388

Paralogs (17): NUAK1 (ENSG00000074590), PRKAA1 (ENSG00000132356), TSSK4 (ENSG00000139908), HUNK (ENSG00000142149), BRSK1 (ENSG00000160469), SIK3 (ENSG00000160584), 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 SIK1 — P57059 (reviewed: P57059)

Alternative names: Salt-inducible kinase 1, Serine/threonine-protein kinase SNF1-like kinase 1

All UniProt accessions (2): P57059, A0A2R8Y6E4

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine-protein kinase involved in various processes such as cell cycle regulation, gluconeogenesis and lipogenesis regulation, muscle growth and differentiation and tumor suppression. Phosphorylates HDAC4, HDAC5, PPME1, SREBF1, CRTC1/TORC1. Inhibits CREB activity by phosphorylating and inhibiting activity of TORCs, the CREB-specific coactivators, like CRTC2/TORC2 and CRTC3/TORC3 in response to cAMP signaling. Acts as a tumor suppressor and plays a key role in p53/TP53-dependent anoikis, a type of apoptosis triggered by cell detachment: required for phosphorylation of p53/TP53 in response to loss of adhesion and is able to suppress metastasis. Part of a sodium-sensing signaling network, probably by mediating phosphorylation of PPME1: following increases in intracellular sodium, SIK1 is activated by CaMK1 and phosphorylates PPME1 subunit of protein phosphatase 2A (PP2A), leading to dephosphorylation of sodium/potassium-transporting ATPase ATP1A1 and subsequent increase activity of ATP1A1. Acts as a regulator of muscle cells by phosphorylating and inhibiting class II histone deacetylases HDAC4 and HDAC5, leading to promote expression of MEF2 target genes in myocytes. Also required during cardiomyogenesis by regulating the exit of cardiomyoblasts from the cell cycle via down-regulation of CDKN1C/p57Kip2. Acts as a regulator of hepatic gluconeogenesis by phosphorylating and repressing the CREB-specific coactivators CRTC1/TORC1 and CRTC2/TORC2, leading to inhibit CREB activity. Also regulates hepatic lipogenesis by phosphorylating and inhibiting SREBF1. In concert with CRTC1/TORC1, regulates the light-induced entrainment of the circadian clock by attenuating PER1 induction; represses CREB-mediated transcription of PER1 by phosphorylating and deactivating CRTC1/TORC1.

Subunit / interactions. Interacts with ATP1A1. Interacts (when phosphorylated on Thr-182 and Ser-186) with YWHAZ. Interacts (when phosphorylated at Thr-473 and/or Ser-575) with 14-3-3 proteins; the interaction inhibits kinase activity towards TORCs. There is a cooperative effect of the phosphorylation sites in 14-3-3 binding as the interaction is stronger when both Thr-473 and Ser-575 are modified.

Subcellular location. Cytoplasm. Nucleus.

Post-translational modifications. Phosphorylated at Thr-182 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39, leading to its activation. Phosphorylation at Thr-182 promotes autophosphorylation at Ser-186, which is required for sustained activity. Autophosphorylation at Ser-186 is maintained by sequential phosphorylation at Thr-182 by GSK3-beta. GSK3-beta cannot initiate phosphorylation at Thr-182, it can only maintain it. Phosphorylation at Ser-575 in response to cAMP signaling promotes translocation to the cytoplasm. Phosphorylation at Thr-322 by CaMK1 following intracellular sodium concentration leads to activation.

Disease relevance. Developmental and epileptic encephalopathy 30 (DEE30) [MIM:616341] A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. The disease is caused by variants affecting the gene represented in this entry. Defects in SIK1 may be associated with some cancers, such as breast cancers. Loss of SIK1 correlates with poor patient outcome in breast cancers.

Activity regulation. Activated by phosphorylation on Thr-182. Also activated by phosphorylation on Thr-322 in response to increases in intracellular sodium in parallel with elevations in intracellular calcium through the reversible sodium/calcium exchanger. Inhibited by phosphorylation at Thr-473 and Ser-575, probably by PKA, which triggers interaction with 14-3-3 proteins.

Domain organisation. The RK-rich region determines the subcellular location and is required for cAMP responsiveness.

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

RefSeq proteins (1): NP_775490* (*=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
IPR017090	Ser/Thr_kinase_SIK1/2	Family
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 (39 total): sequence variant 11, mutagenesis site 11, modified residue 5, region of interest 4, domain 2, sequence conflict 2, binding site 2, chain 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P57059-F1	61.31	0.36

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): 149 (proton acceptor)

Ligand- & substrate-binding residues (2): 33–41; 56

Post-translational modifications (5): 182, 186, 322, 473, 575

Mutagenesis-validated functional residues (11):

Position	Phenotype
56	loss of kinase activity.
135	decreased kinase activity without affecting much autophosphorylation status.
182	prevents phosphorylation and activation by stk11/lkb1 complex. reduced inhibition of crtc3-mediated transcriptional acti
186	impaired autophosphorylation and kinase activity.
186	does not autophosphorylation and kinase activity.
209	decreased kinase activity without affecting much autophosphorylation status.
248	decreased kinase activity without affecting much autophosphorylation status.
473	reduced but still present interaction with 14-3-3 proteins in response to camp signaling and, thus, still able to inhibi
575	loss of interaction with 14-3-3 proteins in response to camp signaling and, thus, still able to inhibit torc activity. r
575	strongly reduced but still present interaction with 14-3-3 proteins in response to camp signaling and, thus, still able

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9931510	Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes
R-HSA-400253

MSigDB gene sets: 496 (showing top): GOBP_CIRCADIAN_RHYTHM, ATF_B, AAGCAAT_MIR137, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_REGULATION_OF_TRIGLYCERIDE_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_LIPID_METABOLIC_PROCESS, GOBP_PHOTOPERIODISM, TTTGTAG_MIR520D, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_LIPID_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_STRIATED_MUSCLE_CELL_DIFFERENTIATION, CREBP1_Q2, NAGASHIMA_NRG1_SIGNALING_UP, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_REGULATION_OF_SODIUM_ION_TRANSPORT

GO Biological Process (17): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of sodium ion transport (GO:0002028), protein phosphorylation (GO:0006468), regulation of mitotic cell cycle (GO:0007346), regulation of myotube differentiation (GO:0010830), negative regulation of triglyceride biosynthetic process (GO:0010868), obsolete negative regulation of CREB transcription factor activity (GO:0032792), intracellular signal transduction (GO:0035556), entrainment of circadian clock by photoperiod (GO:0043153), anoikis (GO:0043276), regulation of cell differentiation (GO:0045595), negative regulation of gluconeogenesis (GO:0045721), protein autophosphorylation (GO:0046777), rhythmic process (GO:0048511), cardiac muscle cell differentiation (GO:0055007), positive regulation of anoikis (GO:2000210), cell differentiation (GO:0030154)

GO Molecular Function (14): magnesium ion binding (GO:0000287), protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), cAMP response element binding protein binding (GO:0008140), protein kinase binding (GO:0019901), histone deacetylase binding (GO:0042826), 14-3-3 protein binding (GO:0071889), 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 (2): nucleus (GO:0005634), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Circadian clock	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular anatomical structure	2
protein kinase activity	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
sodium ion transport	1
regulation of metal ion transport	1
phosphorylation	1
protein modification process	1
mitotic cell cycle	1
regulation of cell cycle	1
myotube differentiation	1
regulation of striated muscle cell differentiation	1
regulation of triglyceride biosynthetic process	1
triglyceride biosynthetic process	1
negative regulation of lipid biosynthetic process	1
negative regulation of triglyceride metabolic process	1
signal transduction	1
photoperiodism	1
entrainment of circadian clock	1
apoptotic process	1
cell differentiation	1
regulation of developmental process	1
regulation of cellular process	1
gluconeogenesis	1
regulation of gluconeogenesis	1
negative regulation of biosynthetic process	1
negative regulation of carbohydrate metabolic process	1
negative regulation of small molecule metabolic process	1
protein phosphorylation	1
biological_process	1
cardiocyte differentiation	1
cardiac muscle tissue development	1
striated muscle cell differentiation	1
positive regulation of apoptotic process	1
anoikis	1
regulation of anoikis	1
cellular developmental process	1
metal ion binding	1
adenyl ribonucleotide binding	1

Protein interactions and networks

STRING

1700 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SIK1	CREB1	P16220	713
SIK1	HDAC5	Q9UQL6	693
SIK1	CRTC3	Q6UUV7	671
SIK1	CRTC2	Q53ET0	668
SIK1	CREM	Q03060	600
SIK1	ISYNA1	Q9NPH2	598
SIK1	CRTC1	Q6UUV9	574
SIK1	ATP1A3	P13637	536
SIK1	ATP1A1	P05023	533
SIK1	ATP1A4	Q13733	511
SIK1	MOB1B	Q7L9L4	487
SIK1	NUAK2	Q9H093	474
SIK1	PCK2	Q16822	460
SIK1	SIK3	Q9Y2K2	458
SIK1	NUP205	Q92621	452

IntAct

38 interactions, top by confidence:

A	B	Type	Score
YWHAZ	MARK3	psi-mi:“MI:0914”(association)	0.940
GINS4	SIK1	psi-mi:“MI:0915”(physical association)	0.800
SIK1	GINS4	psi-mi:“MI:0914”(association)	0.800
YWHAZ	SIK1	psi-mi:“MI:0407”(direct interaction)	0.680
SIK1	YWHAE	psi-mi:“MI:0914”(association)	0.670
SIK1	YWHAE	psi-mi:“MI:0915”(physical association)	0.670
PRTFDC1	SIK1	psi-mi:“MI:0915”(physical association)	0.560
TIMM10	SIK1	psi-mi:“MI:0915”(physical association)	0.560
PITX1	SIK1	psi-mi:“MI:0915”(physical association)	0.560
MESD	SIK1	psi-mi:“MI:0915”(physical association)	0.560
LHX8	SIK1	psi-mi:“MI:0915”(physical association)	0.560
SIK1	CRTC2	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
SFN	SIK1	psi-mi:“MI:0915”(physical association)	0.400
SIK1	E6	psi-mi:“MI:0915”(physical association)	0.370
RPL3	SIK1	psi-mi:“MI:0915”(physical association)	0.370
SIK1	SUPT5H	psi-mi:“MI:0915”(physical association)	0.370
NMNAT1	SIK1	psi-mi:“MI:0915”(physical association)	0.370
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
SIK1	UBE2E1	psi-mi:“MI:0914”(association)	0.350
SIK1	CLTB	psi-mi:“MI:0914”(association)	0.350
SIK1	KLK10	psi-mi:“MI:0914”(association)	0.350
AFG2A	ESYT2	psi-mi:“MI:0914”(association)	0.350
CD247	DDX1	psi-mi:“MI:0914”(association)	0.350
PRTFDC1	SIK1	psi-mi:“MI:0915”(physical association)	0.000
TIMM10	SIK1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (102): SIK1 (Affinity Capture-MS), SIK1 (Affinity Capture-Western), RNF2 (Affinity Capture-Western), SIK1 (Reconstituted Complex), GINS2 (Affinity Capture-MS), SIK2 (Affinity Capture-MS), GINS4 (Affinity Capture-MS), UBE2E1 (Affinity Capture-MS), SIK3 (Affinity Capture-MS), GINS4 (Affinity Capture-Western), FBXO22 (Affinity Capture-MS), GINS4 (Affinity Capture-MS), RPA1 (Affinity Capture-MS), EEF1A1 (Affinity Capture-MS), HIST2H2BE (Affinity Capture-MS)

ESM2 similar proteins: A0AUV4, A0JM98, A1A5Q6, A2KF29, B1WAS2, C0HKC8, C0HKC9, O60285, O70551, O88866, P51957, P57058, P57059, Q2T9U5, Q4R9F7, Q5R7G9, Q5RD27, Q5REX1, Q5XHI9, Q60670, Q641K5, Q66HE5, Q68UT7, Q6IFT4, Q6P3R8, Q6REY9, Q6VZ17, Q80VH0, Q8BI55, Q8BLD6, Q8BZN4, Q8C0N0, Q8C0V7, Q8C0X8, Q8CFH6, Q8NE63, Q8TF76, Q96SB4, Q9H093, Q9H0K1

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

10 interactions.

A	Effect	B	Mechanism
STK11	up-regulates	SIK1	phosphorylation
SIK1	down-regulates	CRTC1	phosphorylation
SIK1	down-regulates	CRTC3	phosphorylation
SIK1	down-regulates	CRTC2	phosphorylation
SIK1	“down-regulates activity”	CRTC2	phosphorylation
STK11	“up-regulates activity”	SIK1	phosphorylation
AKT	“down-regulates activity”	SIK1	phosphorylation
GSK3B	“up-regulates activity”	SIK1	phosphorylation
dabrafenib	“down-regulates activity”	SIK1	“chemical inhibition”

Disease & clinical

Clinical variants and AI predictions

ClinVar

1115 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	4
Uncertain significance	501
Likely benign	449
Benign	54

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
1807697	GRCh37/hg19 21q22.2-22.3(chr21:42046399-45109188)x1	Pathogenic
190105	NM_173354.5(SIK1):c.859C>A (p.Pro287Thr)	Pathogenic
190106	NM_173354.5(SIK1):c.1039G>T (p.Glu347Ter)	Pathogenic
190107	NM_173354.5(SIK1):c.1840C>T (p.Gln614Ter)	Pathogenic
190109	NM_173354.5(SIK1):c.1906G>A (p.Gly636Ser)	Pathogenic
1319806	NM_173354.5(SIK1):c.1150_1151del (p.Phe384fs)	Likely pathogenic
1332903	NM_173354.5(SIK1):c.1153C>T (p.Arg385Ter)	Likely pathogenic
1703110	NM_173354.5(SIK1):c.1839C>A (p.Cys613Ter)	Likely pathogenic
3065091	NM_173354.5(SIK1):c.1373del (p.Gln458fs)	Likely pathogenic

SpliceAI

2082 predictions. Top by Δscore:

Variant	Effect	Δscore
21:43417116:GCCTG:G	acceptor_loss	1.0000
21:43417117:CCTG:C	acceptor_loss	1.0000
21:43417117:CCTGT:C	acceptor_loss	1.0000
21:43417118:C:CC	acceptor_gain	1.0000
21:43417118:CT:C	acceptor_loss	1.0000
21:43417542:CCT:C	donor_gain	1.0000
21:43417561:T:TA	donor_gain	1.0000
21:43417770:CAGCC:C	acceptor_gain	1.0000
21:43417771:AGCC:A	acceptor_gain	1.0000
21:43417772:GCC:G	acceptor_gain	1.0000
21:43417772:GCCC:G	acceptor_loss	1.0000
21:43417773:CC:C	acceptor_gain	1.0000
21:43417773:CCC:C	acceptor_gain	1.0000
21:43417774:CC:C	acceptor_gain	1.0000
21:43417775:C:CC	acceptor_gain	1.0000
21:43417775:C:CG	acceptor_loss	1.0000
21:43417776:T:A	acceptor_loss	1.0000
21:43418539:TACC:T	acceptor_loss	1.0000
21:43418540:ACC:A	acceptor_loss	1.0000
21:43418541:CCTG:C	acceptor_loss	1.0000
21:43419014:CACTT:C	donor_loss	1.0000
21:43419015:ACTTA:A	donor_loss	1.0000
21:43419016:CTTA:C	donor_loss	1.0000
21:43419017:TTACA:T	donor_loss	1.0000
21:43419018:TACAT:T	donor_loss	1.0000
21:43419019:A:AC	donor_gain	1.0000
21:43419019:A:C	donor_loss	1.0000
21:43419020:C:CA	donor_gain	1.0000
21:43419020:C:CT	donor_gain	1.0000
21:43419020:CA:C	donor_gain	1.0000

AlphaMissense

5035 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:43420377:A:G	W277R	1.000
21:43420377:A:T	W277R	1.000
21:43421086:G:C	F224L	1.000
21:43421086:G:T	F224L	1.000
21:43421088:A:G	F224L	1.000
21:43421245:A:G	W208R	1.000
21:43421245:A:T	W208R	1.000
21:43421366:A:C	D167E	1.000
21:43421366:A:T	D167E	1.000
21:43421673:A:G	L155P	1.000
21:43421675:G:C	N154K	1.000
21:43421675:G:T	N154K	1.000
21:43421676:T:C	N154S	1.000
21:43421677:T:C	N154D	1.000
21:43421691:T:A	D149V	1.000
21:43421691:T:G	D149A	1.000
21:43421694:C:G	R148P	1.000
21:43421700:A:T	V146D	1.000
21:43422006:A:T	V102D	1.000
21:43425512:T:A	K56N	1.000
21:43425512:T:G	K56N	1.000
21:43425516:A:T	I55K	1.000
21:43426065:G:C	F38L	1.000
21:43426065:G:T	F38L	1.000
21:43426067:A:G	F38L	1.000
21:43419959:A:G	L340P	0.999
21:43419971:G:T	A336D	0.999
21:43420375:C:A	W277C	0.999
21:43420375:C:G	W277C	0.999
21:43420410:G:T	R266S	0.999

dbSNP variants (sampled 300 via entrez): RS1002225062 (21:43426808 C>G,T), RS1002639958 (21:43415446 C>A,T), RS1002858816 (21:43424103 C>T), RS1003579909 (21:43416663 C>T), RS1004692429 (21:43428322 GCCACACACACACAC>G), RS1005128811 (21:43428100 T>C), RS1005811221 (21:43426128 G>C), RS1006202569 (21:43421538 C>T), RS1006501409 (21:43417833 G>A,C), RS1006861899 (21:43419893 G>A,C), RS1008225892 (21:43416740 C>T), RS1008714399 (21:43423482 C>T), RS1008870146 (21:43428605 T>C), RS1009274600 (21:43417131 G>A), RS1009315829 (21:43428377 A>G,T)

Disease associations

OMIM: gene MIM:605705 | disease phenotypes: MIM:616341

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental and epileptic encephalopathy, 30	Definitive	Autosomal dominant
genetic developmental and epileptic encephalopathy	Strong	Autosomal dominant
early myoclonic encephalopathy	Supportive	Autosomal dominant
infantile spasms	Supportive	Autosomal dominant
generalized epilepsy	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
genetic developmental and epileptic encephalopathy	Limited	AD

Mondo (6): developmental and epileptic encephalopathy, 30 (MONDO:0014595), language disorder (MONDO:0004750), generalized epilepsy (MONDO:0100574), genetic developmental and epileptic encephalopathy (MONDO:0100062), (MONDO:0016022), infantile spasms (MONDO:0018097)

Orphanet (0):

HPO phenotypes

71 total (30 of 71 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000054	Micropenis
HP:0000070	Ureterocele
HP:0000110	Renal dysplasia
HP:0000175	Cleft palate
HP:0000252	Microcephaly
HP:0000340	Sloping forehead
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000707	Abnormality of the nervous system
HP:0000729	Autistic behavior
HP:0000733	Motor stereotypy
HP:0000752	Hyperactivity
HP:0000826	Precocious puberty
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001254	Lethargy
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001266	Choreoathetosis
HP:0001272	Cerebellar atrophy
HP:0001298	Encephalopathy
HP:0001302	Pachygyria
HP:0001332	Dystonia
HP:0001336	Myoclonus
HP:0001337	Tremor
HP:0001344	Absent speech
HP:0001347	Hyperreflexia
HP:0001500	Broad finger
HP:0001508	Failure to thrive

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST003427_65	Alzheimer disease and age of onset	7.000000e-07
GCST004280_75	Diastolic blood pressure	4.000000e-13
GCST004776_28	Systolic blood pressure	2.000000e-09
GCST004777_59	Diastolic blood pressure	2.000000e-09
GCST005038_58	Allergic disease (asthma, hay fever or eczema)	1.000000e-08
GCST006258_18	Diastolic blood pressure	1.000000e-11
GCST006259_24	Systolic blood pressure	3.000000e-14
GCST006986_10	Red vs. brown/black hair color	1.000000e-08
GCST006988_131	Blond vs. brown/black hair color	2.000000e-15
GCST007094_138	Diastolic blood pressure	3.000000e-08
GCST007099_68	Systolic blood pressure	5.000000e-07

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004847	age at onset
EFO:0006336	diastolic blood pressure
EFO:0006335	systolic blood pressure
EFO:0003924	hair color

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D007806	Language Disorders	C10.597.606.150.500; C23.888.592.604.150.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6082 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

19 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 205,093 (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
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1289926	AXITINIB	4	15,732
CHEMBL180022	NERATINIB	4	9,404
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL477772	PAZOPANIB	4	15,540
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL5416410	DASATINIB	4	655
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL603469	LESTAURTINIB	3
CHEMBL1230609	FORETINIB	2	3,096
CHEMBL1721885	SU-014813	2	363
CHEMBL475251	R-406	2	762
CHEMBL572878	TOZASERTIB	2	2,998
CHEMBL1090479	GSK-1070916	1	177
CHEMBL1908397	KW-2449	1	622
CHEMBL259084	MLN-8054	1	2,430
CHEMBL574738	AST-487	1	451

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

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
HG-9-91-01	Inhibition	9.04	pIC50
PF-07899895	Inhibition	8.92	pIC50
GLPG3312	Inhibition	8.7	pIC50
dasatinib	Inhibition	8.52	pIC50
bosutinib	Inhibition	8.52	pIC50
compound 2c [PMID: 24900538]	Inhibition	8.26	pIC50
ARN-3236	Inhibition	7.67	pIC50

Binding affinities (BindingDB)

33 measured of 52 human assays (52 total across all organisms); most potent 33 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
Staurosporine	KD	1.7 nM
methyl 4-[3-(2,6-dimethylphenyl)-7-[3-(hydroxymethyl)-4-(4-methylpiperazin-1-yl)anilino]-2-oxo-4H-pyrimido[4,5-d]pyrimidin-1-yl]butanoate	IC50	2 nM	US-20250340556: PYRIMIDOPYRIMIDONE COMPOUNDS AND METHODS OF USE THEREOF
5-[3-(2,6-dimethylphenyl)-7-[3-(hydroxymethyl)-4-(4-methylpiperazin-1-yl)anilino]-2-oxo-4H-pyrimido[4,5-d]pyrimidin-1-yl]pentanoic acid	IC50	2 nM	US-20250340556: PYRIMIDOPYRIMIDONE COMPOUNDS AND METHODS OF USE THEREOF
US20250340556, Compound SLT-026	IC50	2 nM	US-20250340556: PYRIMIDOPYRIMIDONE COMPOUNDS AND METHODS OF USE THEREOF
US20250340556, Compound SLT-042	IC50	2 nM	US-20250340556: PYRIMIDOPYRIMIDONE COMPOUNDS AND METHODS OF USE THEREOF
4-[3-(2,6-dimethylphenyl)-7-[3-(hydroxymethyl)-4-(4-methylpiperazin-1-yl)anilino]-2-oxo-4H-pyrimido[4,5-d]pyrimidin-1-yl]butanoic acid	IC50	3 nM	US-20250340556: PYRIMIDOPYRIMIDONE COMPOUNDS AND METHODS OF USE THEREOF
US20250340556, Compound SLT-023	IC50	3 nM	US-20250340556: PYRIMIDOPYRIMIDONE COMPOUNDS AND METHODS OF USE THEREOF
3-[3-(2,6-dimethylphenyl)-7-[3-(hydroxymethyl)-4-(4-methylpiperazin-1-yl)anilino]-2-oxo-4H-pyrimido[4,5-d]pyrimidin-1-yl]propanoic acid	IC50	5 nM	US-20250340556: PYRIMIDOPYRIMIDONE COMPOUNDS AND METHODS OF USE THEREOF
US20250340556, Compound SLT-058	IC50	26 nM	US-20250340556: PYRIMIDOPYRIMIDONE COMPOUNDS AND METHODS OF USE THEREOF
BMS-354825	KD	27 nM
1-[3-(1-Hydroxyethyl)-6-[6-[(6-methyl-3-pyridyl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile	IC50	78 nM	US-20250115607: PYRIDINE DERIVATIVES
N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine	KD	150 nM
PKC-412	KD	190 nM
US20250340556, Compound SLT-059	IC50	286 nM	US-20250340556: PYRIMIDOPYRIMIDONE COMPOUNDS AND METHODS OF USE THEREOF
4-[[7-[2,6-bis(fluoranyl)phenyl]-9-chloranyl-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid	KD	300 nM
1-[3-(1-Hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile	IC50	366 nM	US-20250115607: PYRIDINE DERIVATIVES
1-[6-[6-[(6-Methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanol	IC50	396 nM	US-20250115607: PYRIDINE DERIVATIVES
1-[2-(1-Hydroxyethyl)-5-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyrimidin-3-yl]phenyl]-5-methyl-pyrazole-3-carbonitrile	IC50	616 nM	US-20250127780: IMIDAZO[4,5-B]PYRIDINE AND PYRAZOLO[1,5-A]PYRIMIDINE DERIVATIVES AS SIK MODULATORS FOR THE TREATMENT OF RHEUMATOID ARTHRITIS
1-[2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-3-pyridyl]ethanol	IC50	879 nM	US-20250115607: PYRIDINE DERIVATIVES
N-[4-({4-[(3-methyl-1H-pyrazol-5-yl)amino]-6-(4-methylpiperazin-1-yl)pyrimidin-2-yl}sulfanyl)phenyl]cyclopropanecarboxamide	KD	1100 nM
1-[4-[(4-ethyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[[6-(methylamino)-4-pyrimidinyl]oxy]phenyl]urea	KD	1400 nM
5-[(Z)-(5-fluoranyl-2-oxidanylidene-1H-indol-3-ylidene)methyl]-2,4-dimethyl-N-[(2S)-3-morpholin-4-yl-2-oxidanyl-propyl]-1H-pyrrole-3-carboxamide	KD	2600 nM
1-[2-(1-Hydroxyethyl)-5-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-b]pyridin-3-yl]phenyl]-5-methyl-pyrazole-3-carbonitrile	IC50	2800 nM	US-20250127780: IMIDAZO[4,5-B]PYRIDINE AND PYRAZOLO[1,5-A]PYRIMIDINE DERIVATIVES AS SIK MODULATORS FOR THE TREATMENT OF RHEUMATOID ARTHRITIS
5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)-2-methylbenzene-1-sulfonamide	KD	2900 nM
1-Acyl-1H-[1,2,4]triazole-3,5-diamine Analogue 3b	KD	3100 nM
N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	KD	3500 nM
1-[3-Acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile	IC50	4520 nM	US-20250115607: PYRIDINE DERIVATIVES
1-[3-Fluoro-2-(1-hydroxyethyl)-5-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-b]pyridin-3-yl]phenyl]-5-methyl-pyrazole-3-carbonitrile	IC50	6010 nM	US-20250127780: IMIDAZO[4,5-B]PYRIDINE AND PYRAZOLO[1,5-A]PYRIMIDINE DERIVATIVES AS SIK MODULATORS FOR THE TREATMENT OF RHEUMATOID ARTHRITIS
1-[2-(1-Hydroxyethyl)-5-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyrimidin-3-yl]phenyl]-5-methylpyrazole-3-carbonitrile	IC50	14600 nM	US-20250127780: IMIDAZO[4,5-B]PYRIDINE AND PYRAZOLO[1,5-A]PYRIMIDINE DERIVATIVES AS SIK MODULATORS FOR THE TREATMENT OF RHEUMATOID ARTHRITIS
1-[2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-4-[6-(pyridazin-3-ylamino)imidazo[4,5-b]pyridin-3-yl]phenyl]ethanol	IC50	16600 nM	US-20250127780: IMIDAZO[4,5-B]PYRIDINE AND PYRAZOLO[1,5-A]PYRIMIDINE DERIVATIVES AS SIK MODULATORS FOR THE TREATMENT OF RHEUMATOID ARTHRITIS
1-[3-Acetyl-6-[6-(3-methyl-6,7-dihydropyridazino[4,3-b][1,4]oxazin-8-yl)imidazo[4,5-c]pyridin-3-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile	IC50	17400 nM	US-20250115607: PYRIDINE DERIVATIVES
3-[[3-[4-cyano-3-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]phenyl]-5-methoxy-imidazo[4,5-b]pyridin-6-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide	IC50	18600 nM	US-20250127780: IMIDAZO[4,5-B]PYRIDINE AND PYRAZOLO[1,5-A]PYRIMIDINE DERIVATIVES AS SIK MODULATORS FOR THE TREATMENT OF RHEUMATOID ARTHRITIS
1-[3-acetyl-6-[6-[methyl-(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile	IC50	19000 nM	US-20250115607: PYRIDINE DERIVATIVES

ChEMBL bioactivities

186 potent at pChembl≥5 of 187 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.71	IC50	0.193	nM	CHEMBL6159758
9.63	IC50	0.234	nM	CHEMBL6148877
9.41	IC50	0.392	nM	STAUROSPORINE
9.34	IC50	0.458	nM	STAUROSPORINE
9.11	IC50	0.78	nM	CHEMBL6161140
9.05	IC50	0.9	nM	CHEMBL4553284
9.00	IC50	1	nM	DASATINIB
8.87	IC50	1.34	nM	STAUROSPORINE
8.70	IC50	2	nM	CHEMBL5417444
8.70	IC50	2	nM	CHEMBL5438171
8.66	Kd	2.2	nM	STAUROSPORINE
8.52	Kd	3	nM	CHEMBL4465866
8.52	Kd	3	nM	CHEMBL4576489
8.51	IC50	3.1	nM	CHEMBL5405960
8.48	IC50	3.3	nM	CHEMBL6146175
8.41	Kd	3.9	nM	DASATINIB
8.39	IC50	4.1	nM	CHEMBL5427025
8.26	IC50	5.5	nM	CHEMBL2151321
8.24	IC50	5.8	nM	CHEMBL5431938
8.22	IC50	6	nM	CHEMBL5402213
8.21	IC50	6.1	nM	CHEMBL5440720
8.19	IC50	6.5	nM	CHEMBL5407103
8.19	Kd	6.5	nM	CHEMBL386051
8.16	IC50	6.9	nM	CHEMBL5415380
8.14	IC50	7.3	nM	CHEMBL5405960
8.11	IC50	7.7	nM	CHEMBL6160074
8.09	IC50	8.1	nM	CHEMBL5412961
8.00	IC50	10	nM	CHEMBL4875238
8.00	IC50	10	nM	CHEMBL5399976
8.00	IC50	10	nM	CHEMBL5209511
7.97	IC50	10.8	nM	CHEMBL5404502
7.96	Kd	11	nM	CHEMBL5415503
7.92	IC50	12	nM	CHEMBL5090394
7.87	IC50	13.4	nM	CHEMBL4867844
7.84	IC50	14.5	nM	CHEMBL5397288
7.82	Kd	15	nM	TAE-684
7.80	IC50	16	nM	CHEMBL5438704
7.78	IC50	16.8	nM	CHEMBL5405883
7.77	IC50	17	nM	CHEMBL5426204
7.70	IC50	20	nM	CHEMBL4865466
7.70	IC50	20	nM	CHEMBL5401391
7.70	IC50	20.2	nM	CHEMBL5401167
7.70	IC50	20.1	nM	CHEMBL5419476
7.68	IC50	21	nM	CHEMBL4539742
7.67	IC50	21.6	nM	CHEMBL5398906
7.67	IC50	21.6	nM	CHEMBL5420455
7.67	IC50	21.6	nM	CHEMBL4539742
7.66	IC50	22	nM	CHEMBL5430450
7.62	IC50	24	nM	CHEMBL5408557
7.60	IC50	25.3	nM	CHEMBL5415699

PubChem BioAssay actives

146 with measured affinity, of 733 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	2198414: Inhibition of human SIK1 using AMARAASAAALARRR as substrate preincubated for 20 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by radiometric Hot-SpotSM Kinase assay	ic50	0.0004	uM
1-(2,4-dimethoxyphenyl)-3-(2,6-dimethylphenyl)-1-[6-[4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]urea	1992911: Inhibition of GST fused recombinant SIK1 (unknown origin) expressed in HEK293 cells ALNRTSSDSALHRRR as substrate incubated for 1 hr in presence of ATP	ic50	0.0009	uM
N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide	1985482: Inhibition of N-terminal GST-tagged wild type human SIK1 (1 to 783 residues) expressed in baculovirus-infected Sf21 cells using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0020	uM
4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxybenzamide	1992748: Inhibition of SIK1 (unknown origin) using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo assay	ic50	0.0020	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	2017517: Inhibition of SIK1 (unknown origin)	ic50	0.0030	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	1526247: Binding affinity to recombinant full-length N-terminal His-FLAG-tagged SIK1 (unknown origin) expressed in baculovirus infected Sf9 insect cells incubated for 1 hr by TR-FRET assay	kd	0.0030	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]-methylamino]ethoxy]ethoxy]ethoxy]ethyl]propanamide	1526247: Binding affinity to recombinant full-length N-terminal His-FLAG-tagged SIK1 (unknown origin) expressed in baculovirus infected Sf9 insect cells incubated for 1 hr by TR-FRET assay	kd	0.0030	uM
Bosutinib	2017517: Inhibition of SIK1 (unknown origin)	ic50	0.0030	uM
N-[5-[2-cyano-5-(1-methylazetidin-3-yl)oxy-4-pyridinyl]pyrazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide	1985479: Inhibition of SIK1 (unknown origin)	ic50	0.0031	uM
[4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxyphenyl]methanol	1992748: Inhibition of SIK1 (unknown origin) using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo assay	ic50	0.0041	uM
N-[(1S)-1-(5-fluoro-2-pyridinyl)ethyl]-3-(3-propan-2-yloxy-1H-pyrazol-5-yl)imidazo[4,5-b]pyridin-5-amine	692413: Inhibition of SIK	ic50	0.0055	uM
2-(difluoromethoxy)-N-ethyl-4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-6-methoxybenzamide	1992748: Inhibition of SIK1 (unknown origin) using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo assay	ic50	0.0058	uM
8-(4-aminobutyl)-6-[2,5-difluoro-4-(6-methyl-2-pyridinyl)phenyl]-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one	1974601: Inhibition of full length NanoLuc fused SIK1 (unknown origin) transfected in HEK293T cells using NanoBRET NanoGlo substrate incubated for 2 hrs in presence of tracer by NanoBRET assay	ic50	0.0060	uM
N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-(oxan-4-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide	1985482: Inhibition of N-terminal GST-tagged wild type human SIK1 (1 to 783 residues) expressed in baculovirus-infected Sf21 cells using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0061	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	1985479: Inhibition of SIK1 (unknown origin)	ic50	0.0065	uM
6-(2,6-dichlorophenyl)-8-methyl-2-(3-methylsulfanylanilino)pyrido[2,3-d]pyrimidin-7-one	624733: Binding constant for SIK kinase domain	kd	0.0065	uM
2-(difluoromethoxy)-N-ethyl-6-methoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide	1992748: Inhibition of SIK1 (unknown origin) using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo assay	ic50	0.0069	uM
N-cyclopropyl-4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxybenzamide	1992748: Inhibition of SIK1 (unknown origin) using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo assay	ic50	0.0081	uM
3-(2-chloro-6-methylphenyl)-7-[2-methoxy-4-(1-methylpiperidin-4-yl)anilino]-1-(5-methoxy-2-pyridinyl)-4H-pyrimido[4,5-d]pyrimidin-2-one	1992897: Inhibition of SIK1 (unknown origin)	ic50	0.0100	uM
N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(3-morpholin-4-ylanilino)imidazo[1,2-a]pyridin-3-yl]benzamide	1985482: Inhibition of N-terminal GST-tagged wild type human SIK1 (1 to 783 residues) expressed in baculovirus-infected Sf21 cells using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0100	uM
4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide	1985482: Inhibition of N-terminal GST-tagged wild type human SIK1 (1 to 783 residues) expressed in baculovirus-infected Sf21 cells using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0108	uM
N-[3-[2-[2-ethoxy-4-(4-methylpiperazin-1-yl)anilino]-7-oxo-8-[[(2R)-oxolan-2-yl]methyl]pyrido[2,3-d]pyrimidin-6-yl]phenyl]-3-(trifluoromethyl)benzamide	1988552: Binding affinity to SIK (unknown origin) assessed as dissociation constant by KINOME scan assay	kd	0.0110	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	1974601: Inhibition of full length NanoLuc fused SIK1 (unknown origin) transfected in HEK293T cells using NanoBRET NanoGlo substrate incubated for 2 hrs in presence of tracer by NanoBRET assay	ic50	0.0120	uM
4-[5-[1-(cyanomethyl)pyrazol-4-yl]benzimidazol-1-yl]-N-ethyl-2,6-dimethoxybenzamide	1992748: Inhibition of SIK1 (unknown origin) using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo assay	ic50	0.0145	uM
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	624733: Binding constant for SIK kinase domain	kd	0.0150	uM
4-(cyclopropylamino)-N-(2-fluoro-6-methylphenyl)-2-[3-fluoro-4-(4-methylpiperazin-1-yl)anilino]pyrimidine-5-carboxamide	2017517: Inhibition of SIK1 (unknown origin)	ic50	0.0160	uM
N-cyclopropyl-2-(difluoromethoxy)-4-[7-[4-(dimethylamino)piperidin-1-yl]imidazo[1,2-a]pyridin-3-yl]-6-methoxybenzamide	1985482: Inhibition of N-terminal GST-tagged wild type human SIK1 (1 to 783 residues) expressed in baculovirus-infected Sf21 cells using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0168	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	1975695: Inhibition of SIK1 (unknown origin) using AMARA as substrate buffer incubated for 60 mins followed by addition of ADP-Glo reagent further incubated for 60 mins	ic50	0.0170	uM
8-(4-aminobutyl)-6-(2-chlorophenyl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one	1974601: Inhibition of full length NanoLuc fused SIK1 (unknown origin) transfected in HEK293T cells using NanoBRET NanoGlo substrate incubated for 2 hrs in presence of tracer by NanoBRET assay	ic50	0.0200	uM
4-[5-[1-(2-amino-2-oxoethyl)pyrazol-4-yl]benzimidazol-1-yl]-N-ethyl-2,6-dimethoxybenzamide	1992748: Inhibition of SIK1 (unknown origin) using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo assay	ic50	0.0201	uM
N-ethyl-4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxybenzamide	1992748: Inhibition of SIK1 (unknown origin) using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo assay	ic50	0.0202	uM
3-(2,4-dimethoxyphenyl)-4-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridine	1895088: Inhibition of SIK1 (unknown origin)	ic50	0.0210	uM
N-ethyl-4-[5-[1-(2-hydroxyethyl)pyrazol-4-yl]benzimidazol-1-yl]-2,6-dimethoxybenzamide	1985482: Inhibition of N-terminal GST-tagged wild type human SIK1 (1 to 783 residues) expressed in baculovirus-infected Sf21 cells using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0216	uM
3-(3,5-difluoro-2-methoxyphenyl)-5-(1-piperidin-4-ylpyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine	1985479: Inhibition of SIK1 (unknown origin)	ic50	0.0216	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	1975695: Inhibition of SIK1 (unknown origin) using AMARA as substrate buffer incubated for 60 mins followed by addition of ADP-Glo reagent further incubated for 60 mins	ic50	0.0220	uM
4-(cyclobutylamino)-N-(2-fluoro-6-methylphenyl)-2-[3-fluoro-4-(4-methylpiperazin-1-yl)anilino]pyrimidine-5-carboxamide	2017517: Inhibition of SIK1 (unknown origin)	ic50	0.0240	uM
4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxy-N-methylbenzamide	1992748: Inhibition of SIK1 (unknown origin) using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo assay	ic50	0.0253	uM
4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxybenzoic acid	1992748: Inhibition of SIK1 (unknown origin) using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo assay	ic50	0.0264	uM
N-cyclopropyl-4-[7-(3,3-difluoroazetidin-1-yl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxybenzamide	1985482: Inhibition of N-terminal GST-tagged wild type human SIK1 (1 to 783 residues) expressed in baculovirus-infected Sf21 cells using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0270	uM
N-ethyl-2,6-dimethoxy-4-[5-[1-(2-methoxyethyl)pyrazol-4-yl]benzimidazol-1-yl]benzamide	1992748: Inhibition of SIK1 (unknown origin) using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo assay	ic50	0.0316	uM
N-ethyl-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide	1992748: Inhibition of SIK1 (unknown origin) using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo assay	ic50	0.0327	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	1975695: Inhibition of SIK1 (unknown origin) using AMARA as substrate buffer incubated for 60 mins followed by addition of ADP-Glo reagent further incubated for 60 mins	ic50	0.0330	uM
8-[(5-amino-1,3-dioxan-2-yl)methyl]-6-[2-chloro-4-(6-methyl-2-pyridinyl)phenyl]-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one	1974601: Inhibition of full length NanoLuc fused SIK1 (unknown origin) transfected in HEK293T cells using NanoBRET NanoGlo substrate incubated for 2 hrs in presence of tracer by NanoBRET assay	ic50	0.0330	uM
N-ethyl-2,6-dimethoxy-4-[5-[1-(oxan-4-yl)pyrazol-4-yl]benzimidazol-1-yl]benzamide	1992748: Inhibition of SIK1 (unknown origin) using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo assay	ic50	0.0343	uM
N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(1-methylimidazol-4-yl)amino]imidazo[1,2-a]pyridin-3-yl]benzamide	1985482: Inhibition of N-terminal GST-tagged wild type human SIK1 (1 to 783 residues) expressed in baculovirus-infected Sf21 cells using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0386	uM
Fedratinib	624733: Binding constant for SIK kinase domain	kd	0.0390	uM
methyl 4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxybenzoate	1992748: Inhibition of SIK1 (unknown origin) using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo assay	ic50	0.0441	uM
4-[7-(4-acetylpiperazin-1-yl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide	1985482: Inhibition of N-terminal GST-tagged wild type human SIK1 (1 to 783 residues) expressed in baculovirus-infected Sf21 cells using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0449	uM
3-cyano-N-[2,4-difluoro-3-[2-(3-methoxy-1H-pyrazolo[5,4-b]pyridin-5-yl)ethynyl]phenyl]benzenesulfonamide	1486195: Binding affinity to partial length human SIK expressed in Escherichia coli BL21 by active-site-dependent competition assay	kd	0.0450	uM
N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(2-morpholin-4-ylethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide	1985482: Inhibition of N-terminal GST-tagged wild type human SIK1 (1 to 783 residues) expressed in baculovirus-infected Sf21 cells using AMARA peptide as substrate incubated for 120 mins in presence of ATP by ADP-Glo kinase assay	ic50	0.0515	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	5
Cyclosporine	increases expression	3
Acetaminophen	increases expression	2
Benzo(a)pyrene	decreases methylation, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	affects expression, decreases expression	2
Aflatoxin B1	increases expression	2
Particulate Matter	affects cotreatment, increases abundance, increases expression, decreases expression	2
aristolochic acid I	decreases expression	1
chloroacetaldehyde	decreases expression	1
methylmercuric chloride	increases expression	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
trichostatin A	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
nickel chloride	increases expression	1
manganese chloride	decreases expression, increases abundance	1
potassium chromate(VI)	affects cotreatment, increases expression	1
coumarin	increases phosphorylation	1
hydroquinone	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
epigallocatechin gallate	affects cotreatment, increases expression	1
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine	decreases expression	1
perfluoro-n-nonanoic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
torcetrapib	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
PCI 5002	affects cotreatment, increases expression	1
Capecitabine	decreases expression	1

ChEMBL screening assays

210 unique, capped per target: 205 binding, 4 toxicity, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1045665	Binding	Binding affinity to SIK 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
CHEMBL4687869	ADMET	Inhibition of human SIK assessed as residual activity at 10 uM relative to control	Aminothiazolones as potent, selective and cell active inhibitors of the PIM kinase family. — Bioorg Med Chem
CHEMBL5338269	Toxicity	Inhibition of SIK1 (unknown origin) using ALNRTSSDSALHRRR as substrate	Discovery of Clinical Candidate GLPG3970: A Potent and Selective Dual SIK2/SIK3 Inhibitor for the Treatment of Autoimmune and Inflammatory Diseases. — 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_B2FC	Abcam HeLa SIK1 KO	Cancer cell line	Female
CVCL_DX56	HAP1 SIK1 (-) SIK3 (-) 1	Cancer cell line	Male
CVCL_DX57	HAP1 SIK1 (-) SIK3 (-) 2	Cancer cell line	Male
CVCL_TL12	HAP1 SIK1 (-) 1	Cancer cell line	Male
CVCL_XS80	HAP1 SIK1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03590197	PHASE4	COMPLETED	Effect of Melatonin on Seizure Outcome, Neuronal Damage and Quality of Life in Patients With Generalized Epilepsy
NCT01413711	PHASE4	WITHDRAWN	An Open-Label, Single and Multiple Oral Dose Pharmacokinetic Study of Vigabatrin in Infants With Infantile Spasms
NCT02092883	PHASE4	COMPLETED	Evaluation of Neuroinflammation in Children With Infantile Spasms
NCT00150735	PHASE3	COMPLETED	Monotherapy With Levetiracetam in Newly Diagnosed Patients Suffering From Epilepsy
NCT00150748	PHASE3	COMPLETED	Long Term Follow up Treatment With Levetiracetam in Subjects of 4 Years and Older With Generalized Epilepsy
NCT03678753	PHASE3	COMPLETED	Randomized, Double-Blind Study to Evaluate Efficacy and Safety of Cenobamate Adjunctive Therapy in PGTC Seizures
NCT06719141	PHASE3	RECRUITING	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathies (DEE)
NCT06908226	PHASE3	ENROLLING_BY_INVITATION	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathy (DEE)
NCT01575639	PHASE3	COMPLETED	Prednisolone in Infantile Spasms- High Dose Versus Usual Dose
NCT01828437	PHASE3	COMPLETED	Addition of Pyridoxine to Prednisolone in Infantile Spasms
NCT02299115	PHASE3	WITHDRAWN	Prednisolone Versus Vigabatrin in the First-line Treatment of Infantile Spasms
NCT02953548	PHASE3	COMPLETED	Trial of Cannabidiol (CBD; GWP42003-P) for Infantile Spasms (GWPCARE7)
NCT02954887	PHASE3	COMPLETED	Phase 3 Trial of Cannabidiol (CBD; GWP42003-P) for Infantile Spasms: Open-label Extension Phase (GWPCARE7)
NCT00033150	PHASE3	COMPLETED	A Comparison of Language Intervention Programs
NCT06908356	PHASE2	RECRUITING	An Open Label Trial to Evaluate the Efficacy and Safety of PRAX-628 in Adults With Focal Onset or Tonic-Clonic Seizures
NCT05626634	PHASE2	COMPLETED	Open-label, Long-term Safety Study of LP352 in Subjects With Developmental and Epileptic Encephalopathy
NCT00441896	PHASE2	COMPLETED	A Randomized, Controlled Trial of Ganaxolone in Patients With Infantile Spasms
NCT00442104	PHASE2	TERMINATED	Open-label Extension to Protocol 1042-0500
NCT02829827	PHASE2	TERMINATED	A Phase 2 Study of Radiprodil in Subjects With Drug-resistant Infantile Spasms (IS)
NCT03976076	PHASE2	TERMINATED	A Study of Orally Administered JBPOS0101 in Refractory Infantile Spasms Patients
NCT06819670	PHASE2	RECRUITING	A Study to Prevent Infantile Spasms Relapse
NCT00840060	PHASE2	COMPLETED	Efficacy of AMALS in Treating Language Impairment in Children
NCT04060017	PHASE2	ACTIVE_NOT_RECRUITING	Early Treatment of Language Impairment in Young Children With Autism Spectrum Disorder With Leucovorin Calcium
NCT04060030	PHASE2	RECRUITING	Treatment of Social and Language Deficits With Leucovorin for Young Children With Autism
NCT04937452	PHASE2	COMPLETED	Dopaminergic Therapy for Frontotemporal Dementia Patients
NCT06700811	PHASE1	RECRUITING	Ketogenic Diet for Prevention of Epileptic Spasms in Infantile Onset Genetic Epilepsies
NCT06425159	PHASE2/PHASE3	TERMINATED	A Study to Determine if BHV-7000 is Effective and Safe in Adults With Idiopathic Generalized Epilepsy With Generalized Tonic-clonic Seizures
NCT00001325	Not specified	COMPLETED	Metabolic Abnormalities in Children With Epilepsy
NCT01311440	Not specified	COMPLETED	Modified Atkins Diet Treatment for Adults With Drug-resistant Epilepsy
NCT03368469	Not specified	WITHDRAWN	Transcranial Direct Current Stimulation (tDCS) in Children and Adolescents With Epilepsy and Depression
NCT03457961	Not specified	UNKNOWN	Post-market Study of AMPA Receptor Antagonists for Epilepsy Patients in Hong Kong
NCT03955432	Not specified	TERMINATED	Long-term Cardiac Monitoring in Epilepsy
NCT04965571	Not specified	COMPLETED	Clinical Features and Outcome of Wilson’s Disease With Generalized Epilepsy in Chinese Patients
NCT06797791	Not specified	COMPLETED	Assessment of Multifocal Continuous Theta Burst Transcranial Magnetic Stimulation (cTBS) Effects in Generalized Epilepsy Patients.
NCT05364021	PHASE1/PHASE2	COMPLETED	Study to Investigate LP352 in Subjects With Developmental and Epileptic Encephalopathies
NCT06983158	PHASE1/PHASE2	SUSPENDED	A Clinical Trial of CAP-002 Gene Therapy in Pediatric Patients With Syntaxin-Binding Protein 1 (STXBP1) Encephalopathy
NCT04937062	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Phenylbutyrate for Monogenetic Developmental and Epileptic Encephalopathy
NCT06149663	Not specified	AVAILABLE	Intermediate-Size Expanded Access Protocol (EAP) for LP352
NCT06380192	Not specified	RECRUITING	Developmental and Epileptic Encephalopathy of Genetic Etiology: Natural History Through Reuse of Clinical Data
NCT07396883	Not specified	NOT_YET_RECRUITING	Developmental and Epileptic Encephalopathies Diagnosed Via Long-read Genome Sequencing