GSK3A

Summary

GSK3A (glycogen synthase kinase 3 alpha, HGNC:4616) is a protein-coding gene on chromosome 19q13.2, encoding Glycogen synthase kinase-3 alpha (P49840). Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt signaling and regulation of transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), CTNNB1/beta-cateni….

This gene encodes a multifunctional Ser/Thr protein kinase that is implicated in the control of several regulatory proteins including glycogen synthase, and transcription factors, such as JUN. It also plays a role in the WNT and PI3K signaling pathways, as well as regulates the production of beta-amyloid peptides associated with Alzheimer’s disease.

Source: NCBI Gene 2931 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 44 total
• Phenotypes (HPO): 1
• Druggable target: yes — 50 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_019884

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4616
Approved symbol	GSK3A
Name	glycogen synthase kinase 3 alpha
Location	19q13.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000105723
Ensembl biotype	protein_coding
OMIM	606784
Entrez	2931

Gene structure

Transcript identifiers

Ensembl transcripts: 40 — 21 nonsense_mediated_decay, 16 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000222330, ENST00000398249, ENST00000453535, ENST00000493059, ENST00000676517, ENST00000676537, ENST00000676603, ENST00000676676, ENST00000676724, ENST00000676790, ENST00000676845, ENST00000677025, ENST00000677371, ENST00000677424, ENST00000677449, ENST00000677464, ENST00000677469, ENST00000677575, ENST00000677702, ENST00000677735, ENST00000677751, ENST00000677897, ENST00000678008, ENST00000678040, ENST00000678258, ENST00000678276, ENST00000678324, ENST00000678354, ENST00000678427, ENST00000678491, ENST00000678524, ENST00000678672, ENST00000678692, ENST00000678751, ENST00000678936, ENST00000679108, ENST00000679145, ENST00000679257, ENST00000679279, ENST00000679338

RefSeq mRNA: 1 — MANE Select: NM_019884 NM_019884

CCDS: CCDS12599

Canonical transcript exons

ENST00000222330 — 11 exons

Exon	Start	End
ENSE00000709434	42234548	42234678
ENSE00000709435	42234353	42234459
ENSE00000709436	42233286	42233383
ENSE00000709437	42233110	42233205
ENSE00000709438	42232496	42232682
ENSE00001053028	42242183	42242602
ENSE00001824331	42230190	42230867
ENSE00003490358	42236606	42236716
ENSE00003508583	42232057	42232149
ENSE00003581361	42236858	42236941
ENSE00003643441	42239955	42240142

Expression profiles

Bgee: expression breadth ubiquitous, 301 present calls, max score 99.38.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 31.6061 / max 446.2443, expressed in 1819 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
181154	30.4912	1816
181151	0.4846	230
181152	0.3935	189
181153	0.2368	75

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	99.38	gold quality
ganglionic eminence	UBERON:0004023	99.03	gold quality
ventricular zone	UBERON:0003053	98.66	gold quality
right frontal lobe	UBERON:0002810	98.59	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.49	gold quality
cerebellar hemisphere	UBERON:0002245	98.38	gold quality
cerebellar cortex	UBERON:0002129	98.35	gold quality
prefrontal cortex	UBERON:0000451	98.02	gold quality
cingulate cortex	UBERON:0003027	97.94	gold quality
anterior cingulate cortex	UBERON:0009835	97.89	gold quality
granulocyte	CL:0000094	97.88	gold quality
lower esophagus mucosa	UBERON:0035834	97.80	gold quality
colonic epithelium	UBERON:0000397	97.61	gold quality
type B pancreatic cell	CL:0000169	97.54	gold quality
amygdala	UBERON:0001876	97.50	gold quality
adenohypophysis	UBERON:0002196	97.48	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.28	gold quality
metanephros cortex	UBERON:0010533	97.24	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.21	gold quality
nucleus accumbens	UBERON:0001882	97.12	gold quality
left testis	UBERON:0004533	97.12	gold quality
cerebellum	UBERON:0002037	97.10	gold quality
right testis	UBERON:0004534	97.08	gold quality
lower esophagus	UBERON:0013473	97.05	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.05	gold quality
stromal cell of endometrium	CL:0002255	97.03	gold quality
right lobe of thyroid gland	UBERON:0001119	97.03	gold quality
putamen	UBERON:0001874	97.02	gold quality
mucosa of transverse colon	UBERON:0004991	97.02	gold quality
body of uterus	UBERON:0009853	97.00	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.09
E-GEOD-86618	no	21.12
E-MTAB-9801	no	3.67

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
NR3C1	Activation

Upstream regulators (CollecTRI, top): CEBPA, CREB1, NFKB1, NR2C2, RELA, TSC22D3

miRNA regulators (miRDB)

59 targeting GSK3A, 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-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-3617-5P	99.75	69.41	1968
HSA-MIR-641	99.75	69.35	1975
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-182-3P	99.57	67.57	825
HSA-MIR-18A-3P	99.56	65.68	1092
HSA-MIR-302B-5P	99.50	69.49	1857

Literature-anchored findings (GeneRIF, showing 40)

• improves insulin action and glucose metabolism in skeletal muscle (PMID:12086949)
• Paper shows that GSK-3 isoforms are not functionally equivalent in regulating the production of Abeta peptides. siRNA used to knockdown endogenous GSK-3 isoforms in cultured cells. (PMID:12761548)
• GSK3alpha is a potential regulator of platelet function (PMID:14550568)
• Data show that myotubes defective in glycogen synthase (GS) activity express insulin-responsive glycogen synthase kinase-3alpha, suggesting that failure of insulin to decrease GS phosphorylation involves abnormal activity of another kinase or phosphatase. (PMID:15194499)
• Data show that the activity of glycogen synthase kinase-3 (GSK-3) is necessary for the maintenance of the epithelial architecture, and that GSK-3 inhibition stimulates the transcription of Snail (PMID:15631989)
• The results demonstrate that the control of MCL-1 stability by GSK-3 is an important mechanism for the regulation of apoptosis by growth factors, PI3K, and AKT. (PMID:16543145)
• GSK3 alters phosphorylation of CRMP-1, -2, and -4 isoforms (PMID:16611631)
• there is tissue specificity for the regulation of GSK-3 in humans; in skeletal muscle GSK-3 plays a role in control of metabolism and insulin action, whereas the function in adipose tissue is less clear (PMID:16757548)
• Induction of keratinocyte migration is conveyed through EGFR, promoted by endogenous HB-EGF and requires GSK-3alpha activity. (PMID:16806170)
• analysis of critical variations in the function and regulation of GSK-3alpha and GSK-3beta (PMID:16912034)
• These results suggest i) an essential role of PI3K/Akt/GSK-3alpha/beta signaling for a successful replication of VZV and ii) a key function of VZV kinases pORFs 47 and 66 to activate this pathway. (PMID:16934436)
• NT uses PKC-dependent pathways to modulate GSK-3, which may play a role in the NT regulation of intestinal cell growth (PMID:16984735)
• These results indicate that the protein phosphatase-1/inhibitor-2 complex differentially regulates GSK3 dephosphorylation induced by KCl and that GSK3 activity regulates SERCA2 levels. (PMID:16987514)
• S6K1 regulates GSK3 under conditions of mTOR-dependent feedback inhibition of Akt (PMID:17052453)
• Glycogen synthase kinase 3alpha (GSK-3alpha) is identified as a partner for Cdc42 GTPase-activating protein (CdGAP). (PMID:17158447)
• direct regulation of hypoxia-inducible factor 1 alpha subunit stability by GSK-3 may influence physiological processes or pathophysiological situations such as metabolic diseases or tumors (PMID:17325032)
• Reduction of GSK3alpha expression results in improvements in insulin action and elevation of GSK3alpha in human skeletal muscle cells can induce insulin resistance for several responses (PMID:17569761)
• GSK-3 is required for E2-induced ERalpha phosphorylation at Ser-118 and full transcriptional activity of the receptor upon E2 stimulation. (PMID:17609434)
• Maf-transforming activity is controlled by GSK-3-dependent phosphorylation and that phosphorylation by GSK-3 can increase the oncogenic activity of a protein. (PMID:18042454)
• Activin A may mediate ovarian oncogenesis by activating Akt and repressing GSK to stimulate cellular proliferation. (PMID:18450971)
• inhibition of glycogen synthase kinase-3 in androgen-responsive prostate cancer cell lines may reduce AR transcriptional activity and AR protein levels (PMID:18516299)
• GSK-3 and IKK as potential therapeutic targets for pancreatic cancer. (PMID:18829575)
• This review concentrates on the role of protein kinase glycogen synthase kinase 3 in the different types of Alzheimers’ disease. (PMID:18955053)
• The authors found that threonine 10 of H1.5 can be phosphorylated by glycogen synthase kinase-3 in vitro (PMID:19136008)
• Results describe a novel function of chaperonin 10 as a general differentiation factor, not limited to erythroid cells, and show how this biological effect is mediated by GSK-3alpha/beta. (PMID:19142874)
• immunoreactivity of IGF-I and GSK3a/b signaling pathways studied in ALS spinal cords and hippocampus with special reference to Kii and Guam ALS patients: in Japanese ALS patients, IGF-I expression was positively correlated with the clinical duration. (PMID:19323791)
• study suggests that downstream signaling components of the PI3K/Akt pathway, GSK3 & cyclin D2 as well as the significant interaction between PTEN-PDK and between pAkt-pGSK3beta, are involved in the survival and proliferation of leiomyomas. (PMID:19464003)
• Constitutive basal activity of PKR is required for leukemic cell homeostasis and growth and functions as a negative regulator of AKT, thereby increasing the pool of potentially active GSK-3. (PMID:19507191)
• Studies show that GSK-3 and Omi/HtrA2 synergistically cause annexin A2 cleavage and then cell cycle inhibition or apoptosis. (PMID:19656851)
• widely expressed throughout the hair follicles (PMID:19705135)
• GSK-3 interacts with and phosphorylates delta-catenin and thereby negatively affects its stability by enabling its ubiquitination/proteosome-mediated proteolysis (PMID:19706605)
• the N termini of both GSK-3 isoforms were dispensable, whereas progressive C-terminal deletions resulted in protein misfolding exhibited by deficient activity, impaired ability to interact with Axin, and a loss of Tyr(279/216) phosphorylation (PMID:20080974)
• Data identify DEAF1 as an interactor and in vitro substrate of GSK3A and GSK3B that interacts with the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway. (PMID:20368287)
• Glycogen synthase kinase (GSK3) plays a central role in promoting glucocorticoid-induced apoptosis. (PMID:20371704)
• GSK-3 maintains the MLL leukemia stem cell transcriptional program by promoting the conditional association of CREB and its coactivators TORC and CBP with homedomain protein MEIS1, which in turn facilitates HOX-mediated transcription and transformation. (PMID:20541704)
• Investigations with human tissues in this review strongly support the postulate that GSK3 has a pathological role in mood disorders and is likely a therapeutic target in mood disorder treatment. (PMID:20668436)
• Phosphorylation of proteins in the brain associated with Alzheimer’s disease is altered in cortical tissue lacking transgenic glycogen synthase kinase-3alpha and -3ss. (PMID:20831597)
• in multiple myeloma cells GSK-3alpha and beta play distinct roles in cell survival and modulate the sensitivity to proteasome inhibitors (PMID:20920357)
• Data show that the effects of PI3K-Akt signalling on IL-10 responses were mediated at least in part by GSK3. (PMID:21255011)
• GSK3 acts as a molecular brake on the signaling pathway, leading to TF expression in monocytes interacting with activated platelets (PMID:21320285)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	gsk3ab	ENSDARG00000015681
danio_rerio	gsk3aa	ENSDARG00000029501
mus_musculus	Gsk3a	ENSMUSG00000057177
rattus_norvegicus	Gsk3a	ENSRNOG00000020417
drosophila_melanogaster	sgg	FBGN0003371
drosophila_melanogaster	gskt	FBGN0046332
caenorhabditis_elegans	gsk-3	WBGENE00001746

Paralogs (1): GSK3B (ENSG00000082701)

Protein

Protein identifiers

Glycogen synthase kinase-3 alpha — P49840 (reviewed: P49840)

Alternative names: Serine/threonine-protein kinase GSK3A

All UniProt accessions (36): P49840, A0A7I2V2H8, A0A7I2V2J2, A0A7I2V2P0, A0A7I2V2P8, A0A7I2V2P9, A0A7I2V2Q4, A0A7I2V341, A0A7I2V345, A0A7I2V379, A0A7I2V3H9, A0A7I2V3M8, A0A7I2V3W5, A0A7I2V418, A0A7I2V442, A0A7I2V485, A0A7I2V4D4, A0A7I2V4Q6, A0A7I2V4Y3, A0A7I2V4Z1, A0A7I2V511, A0A7I2V553, A0A7I2V5B3, A0A7I2V5D7, A0A7I2V5P6, A0A7I2V5Q2, A0A7I2V5S8, A0A7I2V627, A0A7I2YQ76, A0A7I2YQA1, A0A7I2YQA9, A0A7I2YQJ1, A0A7I2YQM8, A0A7I2YQU7, A0A7I2YQV9, A8MT37

UniProt curated annotations — full annotation on UniProt →

Function. Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt signaling and regulation of transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), CTNNB1/beta-catenin, APC and AXIN1. Requires primed phosphorylation of the majority of its substrates. Contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis. Regulates glycogen metabolism in liver, but not in muscle. May also mediate the development of insulin resistance by regulating activation of transcription factors. In Wnt signaling, regulates the level and transcriptional activity of nuclear CTNNB1/beta-catenin. Facilitates amyloid precursor protein (APP) processing and the generation of APP-derived amyloid plaques found in Alzheimer disease. May be involved in the regulation of replication in pancreatic beta-cells. Is necessary for the establishment of neuronal polarity and axon outgrowth. Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation. Acts as a regulator of autophagy by mediating phosphorylation of KAT5/TIP60 under starvation conditions which activates KAT5/TIP60 acetyltransferase activity and promotes acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer. Negatively regulates extrinsic apoptotic signaling pathway via death domain receptors. Promotes the formation of an anti-apoptotic complex, made of DDX3X, BRIC2 and GSK3B, at death receptors, including TNFRSF10B. The anti-apoptotic function is most effective with weak apoptotic signals and can be overcome by stronger stimulation. Phosphorylates mTORC2 complex component RICTOR at ‘Thr-1695’ which facilitates FBXW7-mediated ubiquitination and subsequent degradation of RICTOR.

Subunit / interactions. Monomer. Interacts with ARRB2. Interacts with AXIN1 and CTNNB1/beta-catenin. Interacts with CTNND2. Interacts with LMBR1L. Interacts with DDX3X. Interacts with TNFRSF10B. Interacts with RICTOR; the interaction results in phosphorylation of RICTOR at ‘Thr-1695’ by GSK3A which facilitates FBXW7-mediated ubiquitination and subsequent degradation of RICTOR. (Microbial infection) Interacts with M.tuberculosis PtpA.

Post-translational modifications. Phosphorylated by AKT1 at Ser-21: upon insulin-mediated signaling, the activated PKB/AKT1 protein kinase phosphorylates and deactivates GSK3A, resulting in the dephosphorylation and activation of GYS1. Activated by phosphorylation at Tyr-279. (Microbial infection) Dephosphorylated at Tyr-279 by M.tuberculosis PtpA, which leads to prevention of apoptosis during early stages of microbial infection.

Activity regulation. Activated by phosphorylation at Tyr-279. In response to insulin, inhibited by phosphorylation at Ser-21 by PKB/AKT1; phosphorylation at this site causes a conformational change, preventing access of substrates to the active site. Inhibited by lithium.

Miscellaneous. Higher expression and activity of GSK3A are found in the skeletal muscle (vastus lateralis) of patients with type 2 diabetes. Several potent GSK3 (GSK3A and GSK3B) inhibitors have been identified and characterized in preclinical models for treatments of type 2 diabetes.

Similarity. Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. GSK-3 subfamily.

RefSeq proteins (1): NP_063937* (*=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
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR039192	STKc_GSK3	Domain
IPR050591	GSK-3	Family

Pfam: PF00069

Enzyme classification (BRENDA):

• EC 2.7.11.26 — tau-protein kinase (BRENDA: 18 organisms, 200 substrates, 549 inhibitors, 0 Km, 0 kcat entries)

Catalyzed reactions (Rhea), 4 shown:

• L-seryl-[tau protein] + ATP = O-phospho-L-seryl-[tau protein] + ADP + H(+) (RHEA:12801)
• 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)
• L-threonyl-[tau protein] + ATP = O-phospho-L-threonyl-[tau protein] + ADP + H(+) (RHEA:53904)

UniProt features (52 total): helix 20, strand 10, modified residue 7, sequence variant 2, region of interest 2, turn 2, compositionally biased region 2, binding site 2, initiator methionine 1, chain 1, sequence conflict 1, domain 1, active site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7SXF	X-RAY DIFFRACTION	1.94
7SXG	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49840-F1	82.24	0.70

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): 244 (proton acceptor)

Ligand- & substrate-binding residues (2): 125–133; 148

Post-translational modifications (7): 2, 2, 21, 72, 77, 97, 279

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-198323	AKT phosphorylates targets in the cytosol
R-HSA-381038	XBP1(S) activates chaperone genes
R-HSA-5674400	Constitutive Signaling by AKT1 E17K in Cancer
R-HSA-9635465	Suppression of apoptosis
R-HSA-9683610	Maturation of nucleoprotein
R-HSA-9694631	Maturation of nucleoprotein

MSigDB gene sets: 487 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_CARBOHYDRATE_TRANSPORT, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_AUTOPHAGY, REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_POLYSACCHARIDE_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_CARDIAC_LEFT_VENTRICLE_MORPHOGENESIS

GO Biological Process (50): regulation of systemic arterial blood pressure (GO:0003073), cardiac left ventricle morphogenesis (GO:0003214), glycogen metabolic process (GO:0005977), nervous system development (GO:0007399), insulin receptor signaling pathway (GO:0008286), positive regulation of autophagy (GO:0010508), positive regulation of gene expression (GO:0010628), regulation of neuron projection development (GO:0010975), Wnt signaling pathway (GO:0016055), cell migration (GO:0016477), viral protein processing (GO:0019082), cell differentiation (GO:0030154), positive regulation of protein ubiquitination (GO:0031398), lipopolysaccharide-mediated signaling pathway (GO:0031663), negative regulation of TOR signaling (GO:0032007), positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), cellular response to insulin stimulus (GO:0032869), cellular response to interleukin-3 (GO:0036016), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), positive regulation of neuron apoptotic process (GO:0043525), negative regulation of glycogen biosynthetic process (GO:0045719), positive regulation of protein catabolic process (GO:0045732), positive regulation of heart contraction (GO:0045823), positive regulation of transcription by RNA polymerase II (GO:0045944), negative regulation of D-glucose import across plasma membrane (GO:0046325), negative regulation of insulin receptor signaling pathway (GO:0046627), excitatory postsynaptic potential (GO:0060079), negative regulation of cell growth involved in cardiac muscle cell development (GO:0061052), regulation of microtubule cytoskeleton organization (GO:0070507), cellular response to lithium ion (GO:0071285), cellular response to glucocorticoid stimulus (GO:0071385), positive regulation of adenylate cyclase-activating adrenergic receptor signaling pathway (GO:0071879), negative regulation of canonical Wnt signaling pathway (GO:0090090), extrinsic apoptotic signaling pathway (GO:0097191), extrinsic apoptotic signaling pathway in absence of ligand (GO:0097192), positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0106071), autosome genomic imprinting (GO:0141068), beta-arrestin-dependent dopamine receptor signaling pathway (GO:0160213), positive regulation of substrate adhesion-dependent cell spreading (GO:1900026), positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway (GO:1901030)

GO Molecular Function (12): protein serine/threonine kinase activity (GO:0004674), signaling receptor binding (GO:0005102), ATP binding (GO:0005524), protein kinase A catalytic subunit binding (GO:0034236), tau protein binding (GO:0048156), 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)

GO Cellular Component (10): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), axon (GO:0030424), beta-catenin destruction complex (GO:0030877), neuronal cell body (GO:0043025), apical dendrite (GO:0097440), postsynapse (GO:0098794), proximal dendrite (GO:1990635)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
PIP3 activates AKT signaling	1
IRE1alpha activates chaperones	1
PI3K/AKT Signaling in Cancer	1
Response of Mtb to phagocytosis	1
Translation of Structural Proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cell surface receptor signaling pathway	2
protein kinase activity	2
intracellular membrane-bounded organelle	2
cytoplasm	2
dendrite	2
regulation of blood pressure	1
cardiac ventricle morphogenesis	1
energy reserve metabolic process	1
glucan metabolic process	1
system development	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to insulin stimulus	1
autophagy	1
positive regulation of catabolic process	1
regulation of autophagy	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
neuron projection development	1
regulation of plasma membrane bounded cell projection organization	1
cell motility	1
viral process	1
viral gene expression	1
cellular developmental process	1
protein ubiquitination	1
regulation of protein ubiquitination	1
positive regulation of protein modification by small protein conjugation or removal	1
cellular response to lipopolysaccharide	1
TOR signaling	1
regulation of TOR signaling	1
negative regulation of intracellular signal transduction	1
regulation of proteasomal ubiquitin-dependent protein catabolic process	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
positive regulation of proteasomal protein catabolic process	1
positive regulation of ubiquitin-dependent protein catabolic process	1
response to insulin	1
cellular response to peptide hormone stimulus	1
response to interleukin-3	1
cellular response to cytokine stimulus	1

Protein interactions and networks

STRING

3530 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GSK3A	AXIN1	O15169	996
GSK3A	APC	P25054	968
GSK3A	CSNK1A1	P48729	968
GSK3A	CTNNB1	P35222	908
GSK3A	APP	P05067	821
GSK3A	TSC2	P49815	699
GSK3A	BTRC	Q9Y297	673
GSK3A	RPS6	P08227	664
GSK3A	MAPT	P10636	659
GSK3A	PHLPP1	O60346	656
GSK3A	PHLPP2	Q6ZVD8	651
GSK3A	GYS1	P13807	650
GSK3A	BBS12	Q6ZW61	638
GSK3A	BBS10	Q8TAM1	635
GSK3A	MCL1	Q07820	628

IntAct

219 interactions, top by confidence:

A	B	Type	Score
CTNNB1	AXIN1	psi-mi:“MI:0914”(association)	0.940
GSK3A	NBR1	psi-mi:“MI:0915”(physical association)	0.840
GSK3A	NBR1	psi-mi:“MI:0217”(phosphorylation reaction)	0.840
NBR1	GSK3A	psi-mi:“MI:0915”(physical association)	0.840
GSKIP	GSK3A	psi-mi:“MI:0915”(physical association)	0.800
GSK3A	AXIN1	psi-mi:“MI:0914”(association)	0.800
GSKIP	GSK3A	psi-mi:“MI:0914”(association)	0.800
APP	MAPT	psi-mi:“MI:0217”(phosphorylation reaction)	0.750
PPP1CB	CCDC85C	psi-mi:“MI:0914”(association)	0.750
FRAT1	GSK3A	psi-mi:“MI:0915”(physical association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
GSK3A	AXIN2	psi-mi:“MI:0915”(physical association)	0.660
GSK3A	FBXO42	psi-mi:“MI:0915”(physical association)	0.660
FBXO42	GSK3A	psi-mi:“MI:0914”(association)	0.660
AXIN2	GSK3A	psi-mi:“MI:0914”(association)	0.660
RCAN1	PPP3CB	psi-mi:“MI:0914”(association)	0.660
GSK3A	DEAF1	psi-mi:“MI:0915”(physical association)	0.650
GSK3A	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.650
GSK3A	LRP6	psi-mi:“MI:0915”(physical association)	0.650
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640

BioGRID (610): GSK3A (Two-hybrid), GSK3A (Affinity Capture-Western), GSK3A (Affinity Capture-MS), GSK3A (Affinity Capture-MS), GSK3A (Affinity Capture-MS), GSK3A (Affinity Capture-MS), RICTOR (Affinity Capture-Western), RICTOR (Biochemical Activity), CTNNB1 (Biochemical Activity), GSK3A (Co-fractionation), AIM1 (Affinity Capture-MS), CTNNA1 (Affinity Capture-MS), CTNNB1 (Affinity Capture-MS), GSK3A (Affinity Capture-MS), AXIN1 (Affinity Capture-MS)

ESM2 similar proteins: A8X5H5, G4NH08, G5EBT1, O04160, O23145, O35831, O44514, P09251, P18265, P18266, P21965, P28926, P32516, P43288, P43289, P49840, P49841, P51137, P51138, P51139, P83101, P84390, Q00536, Q04735, Q10452, Q11179, Q2NL51, Q388M1, Q39010, Q39011, Q39012, Q39019, Q3S406, Q40518, Q5R754, Q5XIT0, Q5YJC2, Q5Z7J0, Q5ZIU3, Q60EZ2

Diamond homologs: A4L9P5, A8WJR8, A8X4H1, A8X5H5, B3WFY8, G5EDB2, O14132, O23145, O43781, O55076, O76039, O88850, O88904, P14680, P18265, P18431, P20911, P22518, P24941, P43288, P43289, P48963, P49657, P49759, P49840, P50613, P51136, P51567, P51568, P51952, P83102, Q00526, Q03147, Q04859, Q07538, Q08DZ2, Q09690, Q09815, Q0IJ08, Q10156

SIGNOR signaling

84 interactions.

A	Effect	B	Mechanism
RPS6KA3	“down-regulates activity”	GSK3A	phosphorylation
PRKCA	down-regulates	GSK3A	phosphorylation
PRKCB	down-regulates	GSK3A	phosphorylation
PRKCD	down-regulates	GSK3A	phosphorylation
PRKCG	down-regulates	GSK3A	phosphorylation
PRKCH	down-regulates	GSK3A	phosphorylation
GSK3A	down-regulates	GYS1	phosphorylation
AKT2	down-regulates	GSK3A	phosphorylation
GSK3A	down-regulates	JUN	phosphorylation
GSK3A	“down-regulates quantity by destabilization”	MYC	phosphorylation
APP	up-regulates	GSK3A
GSK3A	unknown	PKD2	phosphorylation
GSK3A	up-regulates	TSC2	phosphorylation
GSK3A	up-regulates	MAF	phosphorylation
GSK3A	down-regulates	MAF	phosphorylation
GSK3A	“up-regulates activity”	MAFA	phosphorylation
GSK3A	“down-regulates quantity by destabilization”	MAFA	phosphorylation
GSK3A	up-regulates	MAFB	phosphorylation
GSK3A	down-regulates	MAFB	phosphorylation
CAMK2B	down-regulates	GSK3A	phosphorylation
GSK3A	down-regulates	SFPQ	phosphorylation
GSK3A	up-regulates	GSK3A	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 169 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	7	50.8×	3e-08
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	38.4×	2e-06
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	5	32.0×	3e-05
Activation of BH3-only proteins	6	28.4×	6e-06
Intrinsic Pathway for Apoptosis	7	19.5×	7e-06
RHO GTPases activate PKNs	6	18.1×	7e-05
HSF1 activation	5	18.1×	4e-04
Disassembly of the destruction complex and recruitment of AXIN to the membrane	5	17.0×	6e-04

GO biological processes:

GO term	Partners	Fold	FDR
calcineurin-NFAT signaling cascade	5	29.9×	2e-04
cellular response to heat	6	14.6×	1e-03
epidermal growth factor receptor signaling pathway	6	10.6×	4e-03
MAPK cascade	9	9.8×	2e-04
positive regulation of proteasomal ubiquitin-dependent protein catabolic process	6	9.0×	8e-03
canonical Wnt signaling pathway	7	7.6×	7e-03
protein phosphorylation	13	6.3×	2e-04
intracellular protein localization	8	5.9×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	33
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1486 predictions. Top by Δscore:

Variant	Effect	Δscore
19:42232052:CTTA:C	donor_loss	1.0000
19:42232053:TTACC:T	donor_loss	1.0000
19:42232054:TAC:T	donor_loss	1.0000
19:42232056:C:CA	donor_loss	1.0000
19:42232147:GTTC:G	acceptor_loss	1.0000
19:42232148:TT:T	acceptor_gain	1.0000
19:42232148:TTCT:T	acceptor_loss	1.0000
19:42232149:TCTAG:T	acceptor_loss	1.0000
19:42232150:C:CA	acceptor_loss	1.0000
19:42232150:C:CC	acceptor_gain	1.0000
19:42232151:T:A	acceptor_loss	1.0000
19:42233104:CCCCA:C	donor_loss	1.0000
19:42233105:CCCA:C	donor_loss	1.0000
19:42233106:CCACC:C	donor_loss	1.0000
19:42233107:CACCT:C	donor_loss	1.0000
19:42233108:A:C	donor_loss	1.0000
19:42233109:CC:C	donor_loss	1.0000
19:42233145:TGA:T	donor_gain	1.0000
19:42233151:C:CA	donor_gain	1.0000
19:42233201:AGCAC:A	acceptor_gain	1.0000
19:42233202:GCAC:G	acceptor_gain	1.0000
19:42233202:GCACC:G	acceptor_loss	1.0000
19:42233203:CAC:C	acceptor_gain	1.0000
19:42233203:CACC:C	acceptor_gain	1.0000
19:42233204:AC:A	acceptor_gain	1.0000
19:42233205:CC:C	acceptor_gain	1.0000
19:42233206:C:CC	acceptor_gain	1.0000
19:42233207:T:G	acceptor_loss	1.0000
19:42233208:G:GC	acceptor_gain	1.0000
19:42233280:CCTCA:C	donor_loss	1.0000

AlphaMissense

3074 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:42232587:A:C	C398W	1.000
19:42232608:C:A	R391S	1.000
19:42232608:C:G	R391S	1.000
19:42232609:C:A	R391M	1.000
19:42232609:C:G	R391T	1.000
19:42232624:T:C	Y386C	1.000
19:42232625:A:C	Y386D	1.000
19:42232625:A:G	Y386H	1.000
19:42232630:A:G	L384P	1.000
19:42232645:A:G	L379P	1.000
19:42233118:A:G	W364R	1.000
19:42233118:A:T	W364R	1.000
19:42233132:A:C	I359S	1.000
19:42233132:A:G	I359T	1.000
19:42233132:A:T	I359N	1.000
19:42233139:G:A	P357S	1.000
19:42233140:G:C	F356L	1.000
19:42233140:G:T	F356L	1.000
19:42233141:A:C	F356C	1.000
19:42233141:A:G	F356S	1.000
19:42233142:A:C	F356V	1.000
19:42233142:A:G	F356L	1.000
19:42233146:G:C	F354L	1.000
19:42233146:G:T	F354L	1.000
19:42233147:A:G	F354S	1.000
19:42233148:A:G	F354L	1.000
19:42233157:A:G	Y351H	1.000
19:42233164:G:C	N348K	1.000
19:42233164:G:T	N348K	1.000
19:42233166:T:C	N348D	1.000

dbSNP variants (sampled 300 via entrez): RS1000117264 (19:42232813 G>A), RS1000146816 (19:42229743 T>C), RS1000324294 (19:42238462 C>G), RS1000473593 (19:42232387 T>C), RS1000597657 (19:42237731 T>C), RS1000824489 (19:42232753 C>A,T), RS1000943980 (19:42237795 C>T), RS1001014194 (19:42243950 C>T), RS1001623807 (19:42233251 C>T), RS1001632543 (19:42240315 C>G,T), RS1002024269 (19:42240530 C>A,G,T), RS1002026653 (19:42230538 A>G,T), RS1002040368 (19:42234499 G>A,T), RS1002092616 (19:42234162 G>A,C), RS1002208256 (19:42243886 G>A)

Disease associations

OMIM: gene MIM:606784 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): dilated cardiomyopathy (MONDO:0005021)

Orphanet (1): Dilated cardiomyopathy (Orphanet:217604)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0001644	Dilated cardiomyopathy

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010143_27	Meat-related diet	3.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008111	diet measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2095188 (PROTEIN FAMILY), CHEMBL2850 (SINGLE PROTEIN), CHEMBL6177904 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

50 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 233,108 (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
CHEMBL2035187	PACRITINIB	4	3,345
CHEMBL3301610	ABEMACICLIB	4	7,045
CHEMBL3301612	ENCORAFENIB	4	4,624
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL3318007	PIMODIVIR	3	144
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL50	QUERCETIN	3	74,559
CHEMBL85398	THIAZOLIDINEDIONE	3	54,290
CHEMBL2103840	DINACICLIB	3	2,257
CHEMBL300138	ENZASTAURIN	3	3,209
CHEMBL3137331	DEFACTINIB	3	1,229
CHEMBL603469	LESTAURTINIB	3
CHEMBL91829	RUBOXISTAURIN	3	77
CHEMBL1276127	INDIRUBIN	2	181
CHEMBL14762	SELICICLIB	2	3,787
CHEMBL151	LUTEOLIN	2	23,523
CHEMBL31574	FISETIN	2	7,745
CHEMBL1230165	SILMITASERTIB	2	593
CHEMBL1944698	ZOTIRACICLIB	2	2,915
CHEMBL3218578	BGT-226 FREE BASE	2
CHEMBL3544964	RAVOXERTINIB	2
CHEMBL362558	LY-2090314	2
CHEMBL3655762	CYC-065	2
CHEMBL3681949	TOP-1288	2
CHEMBL384304	RG-547	2
CHEMBL3989870	BERZOSERTIB	2
CHEMBL445813	AT-7519	2
CHEMBL4462530	ZEMIRCICLIB	2
CHEMBL475251	R-406	2

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — GSK subfamily

Most potent curated ligand interactions (10 total), top 10:

Ligand	Action	Affinity	Parameter
CHIR-98014	Inhibition	9.19	pIC50
GSK-3 inhibitor IX	Inhibition	8.3	pIC50
AZD1080	Inhibition	8.16	pKi
SB 216763	Inhibition	8.05	pIC50
laduviglusib	Inhibition	8.01	pIC50
GSK-3 inhibitor X	Inhibition	8.0	pIC50
voruciclib	Inhibition	7.77	pIC50
SB-415286	Inhibition	7.42	pIC50
aloisine A	Inhibition	6.3	pIC50
rucaparib metabolite M324	Inhibition	6.24	pIC50

Binding affinities (BindingDB)

1571 measured of 3173 human assays (3176 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-(2-cycloheptyl-6-methylpyrimidin-4-yl)-5-fluoro-2H-pyrazolo[3,4-b]pyridin-3-amine	IC50	0.3 nM	US-8664219: Aminopyrimidines useful as inhibitors of protein kinases
4,7,7-trimethyl-4-phenyl-3-(trifluoromethyl)-2,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-b]quinolin-5-one (BRD1652)	IC50	0.4 nM
N-(2-cyclohexyl-6-methylpyrimidin-4-yl)-5-fluoro-2H-pyrazolo[3,4-b]pyridin-3-amine	IC50	0.5 nM	US-8664219: Aminopyrimidines useful as inhibitors of protein kinases
N-(4,5-dimethyl-6-phenyl-2-pyridinyl)-5-fluoro-2H-pyrazolo[3,4-b]pyridin-3-amine	IC50	0.6 nM	US-8735593: Aminopyridines useful as inhibitors of protein kinases
N-(2-cyclohexyl-5,6-dimethylpyrimidin-4-yl)-5-fluoro-2H-pyrazolo[3,4-b]pyridin-3-amine	IC50	0.7 nM	US-8664219: Aminopyrimidines useful as inhibitors of protein kinases
N-[6-(4,4-difluorocyclohexyl)-2-methylpyrimidin-4-yl]-5-fluoro-2H-pyrazolo[3,4-b]pyridin-3-amine	IC50	1 nM	US-8664219: Aminopyrimidines useful as inhibitors of protein kinases
5-fluoro-N-[6-methyl-2-[(1S,2S)-2-methylcyclohexyl]pyrimidin-4-yl]-2H-pyrazolo[3,4-b]pyridin-3-amine	IC50	1 nM	US-8664219: Aminopyrimidines useful as inhibitors of protein kinases
N-[5-chloro-6-(4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]cyclopropanecarboxamide	IC50	1 nM
N-[5-bromo-6-(4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-1-methylpiperidine-4-carboxamide	IC50	1 nM
Staurosporine	KD	1.7 nM
N-(2-cyclopentyl-6-methylpyrimidin-4-yl)-5-fluoro-2H-pyrazolo[3,4-b]pyridin-3-amine	IC50	2 nM	US-8664219: Aminopyrimidines useful as inhibitors of protein kinases
N-[2-(1-adamantyl)-6-methylpyrimidin-4-yl]-5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine	IC50	2 nM	US-8664219: Aminopyrimidines useful as inhibitors of protein kinases
N-(2-cyclohexyl-6-methylpyrimidin-4-yl)-5-fluoro-1H-indazol-3-amine	IC50	2 nM	US-8664219: Aminopyrimidines useful as inhibitors of protein kinases
N-[6-(2-chlorophenyl)-4-methyl-2-pyridinyl]-5-fluoro-2H-pyrazolo[3,4-b]pyridin-3-amine	IC50	2 nM	US-8735593: Aminopyridines useful as inhibitors of protein kinases
N-[6-(3-bromo-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]cyclopropanecarboxamide	IC50	2 nM
N-[6-(3-chloro-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]cyclopropanecarboxamide	IC50	2 nM
5-fluoro-N-[6-methyl-2-(oxan-4-yl)pyrimidin-4-yl]-2H-pyrazolo[3,4-b]pyridin-3-amine	IC50	3 nM	US-8664219: Aminopyrimidines useful as inhibitors of protein kinases
2-[2-cyclohexyl-6-[(5-fluoro-2H-pyrazolo[3,4-b]pyridin-3-yl)amino]pyrimidin-4-yl]propan-2-ol	IC50	3 nM	US-8664219: Aminopyrimidines useful as inhibitors of protein kinases
N-[6-(2-chlorophenyl)-4-(trifluoromethyl)-2-pyridinyl]-5-fluoro-2H-pyrazolo[3,4-b]pyridin-3-amine	IC50	3 nM	US-8735593: Aminopyridines useful as inhibitors of protein kinases
(R)-4-(2-methoxyphenyl)-7,7-dimethyl-3-(trifluoromethyl)-2,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-b]quinolin-5-one (BRD1172)	IC50	3 nM
4-[[4-[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]naphthalen-1-yl]oxy-2-pyridinyl]amino]-2-methoxy-N-methyl-N-(3-morpholin-4-ylpropyl)benzamide	IC50	5 nM	US-10392346: Kinase inhibitors
1-(3-(tert-Butyldimethylsilyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-(phenylamino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea	IC50	5 nM	US-9783556: Kinase inhibitors
N-{5-phenyl-1H-pyrazolo[3,4-b]pyridin-3-yl}cyclopentanecarboxamide	IC50	5 nM
4-(morpholin-4-yl)-N-{5-phenyl-1H-pyrazolo[3,4-c]pyridazin-3-yl}butanamide	IC50	5 nM
5-(4-ethylpiperazin-1-yl)-N-{5-phenyl-1H-pyrazolo[3,4-c]pyridazin-3-yl}pentanamide	IC50	5 nM
N-[5-(2,3-difluorophenyl)-1H-pyrazolo[3,4-c]pyridazin-3-yl]-4-(dimethylamino)butanamide	IC50	5 nM
N-[5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridazin-3-yl]cyclopropanecarboxamide	KI	5 nM
N-[5-(2,3-difluorophenyl)-1H-pyrazolo[3,4-c]pyridazin-3-yl]cyclopentanecarboxamide	KI	5 nM
pyrazolo[3,4-b]pyridine analogue 8	IC50	5 nM
pyrazolo[3,4-b]pyridine analogue 4	IC50	5 nM
N-[6-(4-hydroxyphenyl)-1H-indazol-3-yl]cyclopropanecarboxamide	IC50	5 nM
N-[6-(4-hydroxyphenyl)-5-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]cyclopropanecarboxamide	IC50	6 nM
(S)-3,7,7-Trimethyl-4-(2-(trifluoromethyl)phenyl)-2,4,6,7,8,9-hexahydro-5Hpyrazolo[3,4-b]quinolin-5-one (14)	IC50	7 nM
1-[4-[2-(1H-indazol-5-ylamino)pyrimidin-4-yl]oxynaphthalen-1-yl]-3-[1-(4-methoxyphenyl)-3-(oxolan-3-yl)pyrazol-5-yl]urea	IC50	7 nM	US-9249125: Pyrazole derivatives as p38 MAP inhibitors
N-[5-(2,3-difluorophenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]butanamide	IC50	7 nM
N-{5-phenyl-1H-pyrazolo[3,4-c]pyridin-3-yl}butanamide	IC50	7 nM
4-(4-ethylpiperazin-1-yl)-N-{5-phenyl-1H-pyrazolo[3,4-c]pyridazin-3-yl}butanamide	IC50	7 nM
(S)-3,4,7,7-tetramethyl-4-phenyl-2,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-b]quinolin-5-one (16)	IC50	8 nM
N-[6-(3,4-dihydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]cyclopropanecarboxamide	IC50	8 nM
1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)- 3-(4-((2-((2-isopropylphenyl)amino) pyrimidin-4-yl)oxy)naphthalen-1-yl)urea	IC50	9 nM	US-9724347: 1-pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl)oxy)napththalen-1-yl) ureas as P38 MAP knase inhibitors
1-methyl-N-{5-phenyl-1H-pyrazolo[3,4-c]pyridazin-3-yl}piperidine-4-carboxamide	IC50	9 nM
N-[6-(2-chlorophenyl)-4,5-dimethyl-2-pyridinyl]-5-fluoro-2H-pyrazolo[3,4-b]pyridin-3-amine	IC50	10 nM	US-8735593: Aminopyridines useful as inhibitors of protein kinases
4-[[4-[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]naphthalen-1-yl]oxy-2-pyridinyl]amino]-2-methoxy-N-[2-(1-methylpiperidin-4-yl)ethyl]benzamide	IC50	10 nM	US-10392346: Kinase inhibitors
4-[[4-[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]naphthalen-1-yl]oxy-2-pyridinyl]amino]-2,6-dimethoxy-N-(2-morpholin-4-ylethyl)benzamide	IC50	10 nM	US-10392346: Kinase inhibitors
N-{5-phenyl-1H-pyrazolo[3,4-c]pyridazin-3-yl}-4-(pyrrolidin-1-yl)butanamide	IC50	11 nM
N-[4-[4-[[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]carbamoylamino]naphthalen-1-yl]oxy-2-pyridinyl]-2-methoxyacetamide	IC50	12 nM	US-9724347: 1-pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl)oxy)napththalen-1-yl) ureas as P38 MAP knase inhibitors
N-[6-(4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-1-methylpiperidine-4-carboxamide	IC50	12 nM
N-[6-(4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]cyclopropanecarboxamide	IC50	13 nM
N-(4-((4-(3-(3-(tert-Butyl)-1-(4-(dimethylphosphoryl)phenyl)-1H-pyrazol-5-yl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)-2-methoxyacetamide	IC50	16 nM	US-9796742: Kinase inhibitors
(S)-3-cyclopropyl-4,7,7-trimethyl-4-phenyl-2,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-b]quinolin-5-one (BRD0209)	IC50	19 nM

ChEMBL bioactivities

2433 potent at pChembl≥5 of 2641 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.15	IC50	0.07	nM	CHEMBL5409061
10.05	IC50	0.09	nM	CHEMBL5270781
10.05	IC50	0.09	nM	CHEMBL5286391
10.00	IC50	0.1	nM	CHEMBL5266553
9.82	IC50	0.15	nM	CHEMBL5437994
9.82	IC50	0.15	nM	CHEMBL5428013
9.80	IC50	0.16	nM	CHEMBL5416472
9.80	IC50	0.16	nM	CHEMBL5440672
9.77	IC50	0.17	nM	CHEMBL5268185
9.77	IC50	0.17	nM	CHEMBL5418606
9.74	IC50	0.18	nM	CHEMBL5282376
9.74	IC50	0.18	nM	CHEMBL5422776
9.72	IC50	0.19	nM	CHEMBL5414726
9.72	IC50	0.19	nM	CHEMBL5407971
9.68	IC50	0.21	nM	CHEMBL5282319
9.66	IC50	0.22	nM	CHEMBL5270555
9.66	IC50	0.22	nM	CHEMBL5436595
9.64	IC50	0.23	nM	CHEMBL5283650
9.62	IC50	0.24	nM	CHEMBL5282654
9.60	IC50	0.25	nM	CHEMBL5419652
9.59	IC50	0.26	nM	CHEMBL5422112
9.55	IC50	0.28	nM	CHEMBL5290300
9.52	IC50	0.3	nM	CHEMBL3652543
9.52	IC50	0.3	nM	CHEMBL5414551
9.52	IC50	0.3	nM	CHEMBL5435368
9.51	IC50	0.31	nM	CHEMBL5424348
9.49	IC50	0.32	nM	CHEMBL5288788
9.47	IC50	0.34	nM	CHEMBL5316226
9.47	IC50	0.34	nM	CHEMBL5273872
9.46	IC50	0.35	nM	CHEMBL5270781
9.46	IC50	0.35	nM	CHEMBL5404581
9.46	IC50	0.35	nM	CHEMBL5404070
9.42	IC50	0.38	nM	CHEMBL5273327
9.40	IC50	0.4	nM	CHEMBL5200578
9.40	IC50	0.4	nM	CHEMBL5285386
9.40	IC50	0.4	nM	CHEMBL5438689
9.39	IC50	0.41	nM	CHEMBL5290040
9.36	IC50	0.44	nM	CHEMBL5274844
9.35	IC50	0.45	nM	CHEMBL5269649
9.35	IC50	0.45	nM	CHEMBL5402829
9.30	IC50	0.5	nM	CHEMBL3652545
9.25	IC50	0.56	nM	CHEMBL5417065
9.24	IC50	0.57	nM	CHEMBL5286737
9.22	IC50	0.6	nM	CHEMBL3661033
9.22	IC50	0.6	nM	CHEMBL4856177
9.22	Ki	0.6	nM	CHEMBL5174733
9.20	IC50	0.63	nM	CHEMBL5401931
9.19	IC50	0.65	nM	CHEMBL1080901
9.18	IC50	0.66	nM	CHEMBL5265990
9.16	IC50	0.69	nM	CHEMBL5410129

PubChem BioAssay actives

1121 with measured affinity, of 2824 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-anilino-N-[4-(4,4-difluoropiperidin-1-yl)-3-pyridinyl]pyrimidine-4-carboxamide	1990477: Displacement of FL-KRREILSRRP[ps]ERYR-NH2 from human recombinant full length GST-tagged GSK-3-alpha expressed in insect cells incubated for 20 hrs by fluorescence based analysis	ic50	0.0001	uM
2-(4-cyanoanilino)-N-[4-(2,2,2-trifluoroethoxy)-3-pyridinyl]pyrimidine-4-carboxamide	1990477: Displacement of FL-KRREILSRRP[ps]ERYR-NH2 from human recombinant full length GST-tagged GSK-3-alpha expressed in insect cells incubated for 20 hrs by fluorescence based analysis	ic50	0.0001	uM
2-phenyl-N-[4-(2,2,2-trifluoroethoxy)-3-pyridinyl]imidazo[1,2-b]pyridazine-8-carboxamide	1948326: Inhibition of full length GST-tagged human recombinant GSK3-alpha using FL-KRREILSRRP[ps]ERYR-NH2 as substrate incubated for 20 hrs	ic50	0.0001	uM
N-[4-(2-methylmorpholin-4-yl)-3-pyridinyl]-2-phenylimidazo[1,2-b]pyridazine-8-carboxamide	1934089: Inhibition of GSK3alpha (unknown origin)	ic50	0.0001	uM
2-(4-cyanoanilino)-N-[4-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]pyrimidine-4-carboxamide	1990477: Displacement of FL-KRREILSRRP[ps]ERYR-NH2 from human recombinant full length GST-tagged GSK-3-alpha expressed in insect cells incubated for 20 hrs by fluorescence based analysis	ic50	0.0001	uM
N-[4-[(2S)-2-methylmorpholin-4-yl]-3-pyridinyl]-2-phenylimidazo[1,2-b]pyridazine-8-carboxamide	1948326: Inhibition of full length GST-tagged human recombinant GSK3-alpha using FL-KRREILSRRP[ps]ERYR-NH2 as substrate incubated for 20 hrs	ic50	0.0001	uM
N-(5-pyridin-3-yl-1H-pyrazolo[3,4-c]pyridazin-3-yl)cyclopropanecarboxamide	1796178: Kinase Inhibition SPA Assay from Article 10.1016/s0960-894x(03)00135-5: “5-aryl-pyrazolo[3,4-b]pyridazines: potent inhibitors of glycogen synthase kinase-3 (GSK-3).”	ki	0.0001	uM
N-[5-(2,3-difluorophenyl)-1H-pyrazolo[3,4-c]pyridazin-3-yl]cyclopentanecarboxamide	1796178: Kinase Inhibition SPA Assay from Article 10.1016/s0960-894x(03)00135-5: “5-aryl-pyrazolo[3,4-b]pyridazines: potent inhibitors of glycogen synthase kinase-3 (GSK-3).”	ki	0.0001	uM
2-(cyclopropanecarbonylamino)-N-[4-[4-fluoro-2-(trifluoromethyl)phenyl]-3-pyridinyl]pyridine-4-carboxamide	1949079: Inhibition of GST tagged GSK-3alpha (unknown origin) incubated for 1 hrs by HTRF assay	ic50	0.0002	uM
2-(4-methylsulfonylanilino)-N-(4-phenyl-3-pyridinyl)pyrimidine-4-carboxamide	1990477: Displacement of FL-KRREILSRRP[ps]ERYR-NH2 from human recombinant full length GST-tagged GSK-3-alpha expressed in insect cells incubated for 20 hrs by fluorescence based analysis	ic50	0.0002	uM
2-(3-chloro-4-cyanoanilino)-N-(4-phenyl-3-pyridinyl)pyrimidine-4-carboxamide	1990477: Displacement of FL-KRREILSRRP[ps]ERYR-NH2 from human recombinant full length GST-tagged GSK-3-alpha expressed in insect cells incubated for 20 hrs by fluorescence based analysis	ic50	0.0002	uM
2-(3-fluoro-4-methoxyanilino)-N-(4-phenyl-3-pyridinyl)pyrimidine-4-carboxamide	1990477: Displacement of FL-KRREILSRRP[ps]ERYR-NH2 from human recombinant full length GST-tagged GSK-3-alpha expressed in insect cells incubated for 20 hrs by fluorescence based analysis	ic50	0.0002	uM
N-(4-morpholin-4-yl-3-pyridinyl)-2-phenylimidazo[1,2-b]pyridazine-8-carboxamide	1948326: Inhibition of full length GST-tagged human recombinant GSK3-alpha using FL-KRREILSRRP[ps]ERYR-NH2 as substrate incubated for 20 hrs	ic50	0.0002	uM
2-phenyl-N-(4-piperidin-1-yl-3-pyridinyl)imidazo[1,2-b]pyridazine-8-carboxamide	1948326: Inhibition of full length GST-tagged human recombinant GSK3-alpha using FL-KRREILSRRP[ps]ERYR-NH2 as substrate incubated for 20 hrs	ic50	0.0002	uM
N-(4-morpholin-4-yl-3-pyridinyl)-2-[4-(trifluoromethyl)phenyl]imidazo[1,2-b]pyridazine-8-carboxamide	1948326: Inhibition of full length GST-tagged human recombinant GSK3-alpha using FL-KRREILSRRP[ps]ERYR-NH2 as substrate incubated for 20 hrs	ic50	0.0002	uM
2-cyclopropyl-N-[4-(4,4-difluoropiperidin-1-yl)-3-pyridinyl]imidazo[1,2-b]pyridazine-8-carboxamide	1948326: Inhibition of full length GST-tagged human recombinant GSK3-alpha using FL-KRREILSRRP[ps]ERYR-NH2 as substrate incubated for 20 hrs	ic50	0.0002	uM
N-[4-(4,4-difluoropiperidin-1-yl)-3-pyridinyl]-2-phenylimidazo[1,2-b]pyridazine-8-carboxamide	1948326: Inhibition of full length GST-tagged human recombinant GSK3-alpha using FL-KRREILSRRP[ps]ERYR-NH2 as substrate incubated for 20 hrs	ic50	0.0002	uM
2-anilino-N-[4-(4-fluorophenyl)-3-pyridinyl]pyrimidine-4-carboxamide	1990477: Displacement of FL-KRREILSRRP[ps]ERYR-NH2 from human recombinant full length GST-tagged GSK-3-alpha expressed in insect cells incubated for 20 hrs by fluorescence based analysis	ic50	0.0002	uM
N-[4-(2,2,2-trifluoroethoxy)-3-pyridinyl]-2-[4-(trifluoromethyl)anilino]pyrimidine-4-carboxamide	1990477: Displacement of FL-KRREILSRRP[ps]ERYR-NH2 from human recombinant full length GST-tagged GSK-3-alpha expressed in insect cells incubated for 20 hrs by fluorescence based analysis	ic50	0.0002	uM
2-(4-methylanilino)-N-(4-phenyl-3-pyridinyl)pyrimidine-4-carboxamide	1990477: Displacement of FL-KRREILSRRP[ps]ERYR-NH2 from human recombinant full length GST-tagged GSK-3-alpha expressed in insect cells incubated for 20 hrs by fluorescence based analysis	ic50	0.0002	uM
2-anilino-N-[4-(2,2,2-trifluoroethoxy)-3-pyridinyl]pyrimidine-4-carboxamide	1990477: Displacement of FL-KRREILSRRP[ps]ERYR-NH2 from human recombinant full length GST-tagged GSK-3-alpha expressed in insect cells incubated for 20 hrs by fluorescence based analysis	ic50	0.0002	uM
N-[5-(2,3-difluorophenyl)-1H-pyrazolo[3,4-c]pyridazin-3-yl]-2-(1-ethylpiperidin-4-yl)acetamide	1796178: Kinase Inhibition SPA Assay from Article 10.1016/s0960-894x(03)00135-5: “5-aryl-pyrazolo[3,4-b]pyridazines: potent inhibitors of glycogen synthase kinase-3 (GSK-3).”	ki	0.0002	uM
N-[4-(2-chloro-4-fluorophenyl)-3-pyridinyl]-2-(cyclopropanecarbonylamino)pyridine-4-carboxamide	1949079: Inhibition of GST tagged GSK-3alpha (unknown origin) incubated for 1 hrs by HTRF assay	ic50	0.0003	uM
2-(cyclopropanecarbonylamino)-N-[4-(2,4-difluorophenyl)-3-pyridinyl]pyridine-4-carboxamide	1949079: Inhibition of GST tagged GSK-3alpha (unknown origin) incubated for 1 hrs by HTRF assay	ic50	0.0003	uM
2-(4-cyanoanilino)-N-(4-phenyl-3-pyridinyl)pyrimidine-4-carboxamide	1990477: Displacement of FL-KRREILSRRP[ps]ERYR-NH2 from human recombinant full length GST-tagged GSK-3-alpha expressed in insect cells incubated for 20 hrs by fluorescence based analysis	ic50	0.0003	uM
N-[4-[(3S)-3-methylmorpholin-4-yl]-3-pyridinyl]-2-phenylimidazo[1,2-b]pyridazine-8-carboxamide	1948326: Inhibition of full length GST-tagged human recombinant GSK3-alpha using FL-KRREILSRRP[ps]ERYR-NH2 as substrate incubated for 20 hrs	ic50	0.0003	uM
2-(4-chloroanilino)-N-(4-phenyl-3-pyridinyl)pyrimidine-4-carboxamide	1990477: Displacement of FL-KRREILSRRP[ps]ERYR-NH2 from human recombinant full length GST-tagged GSK-3-alpha expressed in insect cells incubated for 20 hrs by fluorescence based analysis	ic50	0.0003	uM
2-(4-cyanoanilino)-N-[4-(4-fluorophenyl)-3-pyridinyl]pyrimidine-4-carboxamide	1990477: Displacement of FL-KRREILSRRP[ps]ERYR-NH2 from human recombinant full length GST-tagged GSK-3-alpha expressed in insect cells incubated for 20 hrs by fluorescence based analysis	ic50	0.0003	uM
2-anilino-N-(4-phenyl-3-pyridinyl)pyrimidine-4-carboxamide	1990477: Displacement of FL-KRREILSRRP[ps]ERYR-NH2 from human recombinant full length GST-tagged GSK-3-alpha expressed in insect cells incubated for 20 hrs by fluorescence based analysis	ic50	0.0003	uM
2-(4-cyano-2-methylanilino)-N-(4-phenyl-3-pyridinyl)pyrimidine-4-carboxamide	1990477: Displacement of FL-KRREILSRRP[ps]ERYR-NH2 from human recombinant full length GST-tagged GSK-3-alpha expressed in insect cells incubated for 20 hrs by fluorescence based analysis	ic50	0.0003	uM
2-[4-(difluoromethoxy)anilino]-N-(4-phenyl-3-pyridinyl)pyrimidine-4-carboxamide	1990477: Displacement of FL-KRREILSRRP[ps]ERYR-NH2 from human recombinant full length GST-tagged GSK-3-alpha expressed in insect cells incubated for 20 hrs by fluorescence based analysis	ic50	0.0003	uM
2-[4-(difluoromethoxy)anilino]-N-[4-(4-fluorophenyl)-3-pyridinyl]pyrimidine-4-carboxamide	1990477: Displacement of FL-KRREILSRRP[ps]ERYR-NH2 from human recombinant full length GST-tagged GSK-3-alpha expressed in insect cells incubated for 20 hrs by fluorescence based analysis	ic50	0.0003	uM
N-[4-[(2R)-2-methylmorpholin-4-yl]-3-pyridinyl]-2-phenylimidazo[1,2-b]pyridazine-8-carboxamide	1948326: Inhibition of full length GST-tagged human recombinant GSK3-alpha using FL-KRREILSRRP[ps]ERYR-NH2 as substrate incubated for 20 hrs	ic50	0.0003	uM
2-(cyclopropanecarbonylamino)-N-[4-(4-methoxyphenyl)-3-pyridinyl]pyridine-4-carboxamide	1949079: Inhibition of GST tagged GSK-3alpha (unknown origin) incubated for 1 hrs by HTRF assay	ic50	0.0004	uM
(4R)-4,7,7-trimethyl-4-phenyl-3-(trifluoromethyl)-1,2,3,3a,6,8,9,9a-octahydropyrazolo[3,4-b]quinolin-5-one	1801785: Mobility Shift Microfluidics Assay from Article 10.1021/acschembio.6b00306: “Inhibitors of Glycogen Synthase Kinase 3 with Exquisite Kinome-Wide Selectivity and Their Functional Effects.”	ic50	0.0004	uM
2-phenyl-N-(4-propan-2-yloxy-3-pyridinyl)imidazo[1,2-b]pyridazine-8-carboxamide	1948326: Inhibition of full length GST-tagged human recombinant GSK3-alpha using FL-KRREILSRRP[ps]ERYR-NH2 as substrate incubated for 20 hrs	ic50	0.0004	uM
N-(4-methylsulfonyl-3-pyridinyl)-2-phenylimidazo[1,2-b]pyridazine-8-carboxamide	1948326: Inhibition of full length GST-tagged human recombinant GSK3-alpha using FL-KRREILSRRP[ps]ERYR-NH2 as substrate incubated for 20 hrs	ic50	0.0004	uM
2-cyclopropyl-N-[4-(4-fluorophenyl)-3-pyridinyl]imidazo[1,2-b]pyridazine-8-carboxamide	1948326: Inhibition of full length GST-tagged human recombinant GSK3-alpha using FL-KRREILSRRP[ps]ERYR-NH2 as substrate incubated for 20 hrs	ic50	0.0004	uM
2-(4-methoxyanilino)-N-(4-phenyl-3-pyridinyl)pyrimidine-4-carboxamide	1990477: Displacement of FL-KRREILSRRP[ps]ERYR-NH2 from human recombinant full length GST-tagged GSK-3-alpha expressed in insect cells incubated for 20 hrs by fluorescence based analysis	ic50	0.0004	uM
2-(4-fluoroanilino)-N-[4-(4-fluorophenyl)-3-pyridinyl]pyrimidine-4-carboxamide	1990477: Displacement of FL-KRREILSRRP[ps]ERYR-NH2 from human recombinant full length GST-tagged GSK-3-alpha expressed in insect cells incubated for 20 hrs by fluorescence based analysis	ic50	0.0004	uM
(4S)-4,7,7-trimethyl-4-phenyl-3-(trifluoromethyl)-2,6,8,9-tetrahydropyrazolo[3,4-b]quinolin-5-one	1894049: Inhibition of GSK3alpha (unknown origin) by ADP-glo analysis	ic50	0.0004	uM
2-(2-methoxyphenyl)-N-[4-(2-methylmorpholin-4-yl)-3-pyridinyl]imidazo[1,2-b]pyridazine-8-carboxamide	1948326: Inhibition of full length GST-tagged human recombinant GSK3-alpha using FL-KRREILSRRP[ps]ERYR-NH2 as substrate incubated for 20 hrs	ic50	0.0004	uM
2-anilino-N-[4-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]pyrimidine-4-carboxamide	1990477: Displacement of FL-KRREILSRRP[ps]ERYR-NH2 from human recombinant full length GST-tagged GSK-3-alpha expressed in insect cells incubated for 20 hrs by fluorescence based analysis	ic50	0.0006	uM
N-(4-phenyl-3-pyridinyl)-2-(pyridin-4-ylamino)pyrimidine-4-carboxamide	1990477: Displacement of FL-KRREILSRRP[ps]ERYR-NH2 from human recombinant full length GST-tagged GSK-3-alpha expressed in insect cells incubated for 20 hrs by fluorescence based analysis	ic50	0.0006	uM
N-[4-(2-methylmorpholin-4-yl)-3-pyridinyl]-2-[4-(trifluoromethyl)phenyl]imidazo[1,2-b]pyridazine-8-carboxamide	1948326: Inhibition of full length GST-tagged human recombinant GSK3-alpha using FL-KRREILSRRP[ps]ERYR-NH2 as substrate incubated for 20 hrs	ic50	0.0006	uM
4-(4-methylpiperazin-1-yl)-N-[4-(2-methyl-3-propan-2-ylindazol-5-yl)pyrimidin-2-yl]quinolin-7-amine	1771114: Inhibition of human GSK3A using YRRAAVPPSPSLSRHSSPHQ(pS)EDEEE as substrate incubated for 2 hrs by [gamma-33P]-ATP assay	ic50	0.0006	uM
1-(7-(111C)methoxyquinolin-4-yl)-3-[3-(trifluoromethyl)phenyl]urea	1896092: Binding affinity to GSK-3 (unknown origin) assessed as inhibition constant	ki	0.0006	uM
6-N-[2-[[4-(2,4-dichlorophenyl)-5-(1H-imidazol-2-yl)pyrimidin-2-yl]amino]ethyl]-3-nitropyridine-2,6-diamine	512483: Inhibition of GSK3alpha	ic50	0.0006	uM
2-(cyclopropanecarbonylamino)-N-[4-[2-(trifluoromethyl)phenyl]-3-pyridinyl]pyridine-4-carboxamide	1949079: Inhibition of GST tagged GSK-3alpha (unknown origin) incubated for 1 hrs by HTRF assay	ic50	0.0007	uM
2-(cyclopropanecarbonylamino)-N-[4-(2,2-dimethylpropoxy)-3-pyridinyl]pyridine-4-carboxamide	1949079: Inhibition of GST tagged GSK-3alpha (unknown origin) incubated for 1 hrs by HTRF assay	ic50	0.0007	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases reaction, decreases expression, affects cotreatment, increases abundance, increases expression (+1 more)	6
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	decreases phosphorylation, increases activity, decreases reaction, increases phosphorylation	3
Cadmium Chloride	decreases expression, increases abundance, increases phosphorylation	3
bisphenol F	increases expression, affects cotreatment	2
bisphenol A	increases expression, increases phosphorylation	2
cyanoginosin LR	decreases activity, increases phosphorylation, increases reaction	2
Resveratrol	decreases reaction, increases phosphorylation, decreases phosphorylation, increases activity	2
Paraquat	decreases expression, increases reaction, increases phosphorylation	2
Ruthenium Compounds	decreases activity	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
moringin	affects cotreatment, increases expression	1
WZ35 compound	increases phosphorylation	1
beta-N-methylamino-L-alanine	increases expression, decreases reaction	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
propylparaben	increases expression	1
lead acetate	increases expression	1
methylparaben	increases expression	1
4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone	increases activity, increases phosphorylation	1
tetrabromobisphenol A	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
coumarin	decreases phosphorylation	1
phenanthrene	decreases expression	1
perfluorodecanoic acid	decreases expression	1
epigallocatechin gallate	increases phosphorylation	1
fenugreek seed meal	increases phosphorylation	1
sphingosine 1-phosphate	decreases reaction, increases expression	1
N-acetylsphingosine	decreases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1

ChEMBL screening assays

676 unique, capped per target: 667 binding, 9 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1032325	Binding	Inhibition of GSK3-mediated beta-casein phosphorylation in human SH-SY5Y cells in presence of MG132 by Western blot analysis	Soluble 3’,6-substituted indirubins with enhanced selectivity toward glycogen synthase kinase -3 alter circadian period. — J Med Chem
CHEMBL709400	Functional	Inhibition of glycogen synthesis in rat skeletal muscle L6 cells	Novel GSK-3 inhibitors with improved cellular activity. — Bioorg Med Chem Lett

Cellosaurus cell lines

5 cell lines: 3 cancer cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2YA	Abcam HEK293T GSK3A KO	Transformed cell line	Female
CVCL_D1T3	Abcam U-87MG GSK3A KO	Cancer cell line	Male
CVCL_D9FZ	Ubigene HEK293 GSK3A KO	Transformed cell line	Female
CVCL_SQ64	HAP1 GSK3A (-) 1	Cancer cell line	Male
CVCL_SQ65	HAP1 GSK3A (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00374465	PHASE4	UNKNOWN	Therapy With Verapamil or Carvedilol in Chronic Heart Failure
NCT01293903	PHASE4	COMPLETED	Study of Qiliqiangxin Capsule to Treat Dilated Cardiomyopathy
NCT01557140	PHASE4	COMPLETED	A Randomized Trial of Carvedilol in Chronic Chagas Cardiomyopathy
NCT01917149	PHASE4	COMPLETED	Supramaximal Titrated Inhibition of RAAS in Dilated Cardiomyopathy
NCT02115581	PHASE4	COMPLETED	Coenzyme Q10 Supplementation in Children With Idiopathic Dilated Cardiomyopathy
NCT06236022	PHASE4	RECRUITING	The Effects of Sirolimus in Patients With Dilated Cardiomyopathy Infected With Kaposi Sarcoma-associated Virus
NCT00333827	PHASE3	COMPLETED	Cell Therapy In Dilated Cardiomyopathy
NCT00505154	PHASE3	COMPLETED	Effect of Rosuvastatin on Left Ventricular Remodeling
NCT01223703	PHASE3	COMPLETED	PUFAs and Left Ventricular Function in Heart Failure
NCT01583114	PHASE3	TERMINATED	PREclinical Mutation CARriers From Families With DIlated Cardiomyopathy and ACE Inhibitors
NCT01914081	PHASE3	UNKNOWN	Resveratrol: A Potential Anti- Remodeling Agent in Heart Failure, From Bench to Bedside
NCT02989181	PHASE3	UNKNOWN	Continues Positive Airway Pressure Treatment for Patients With Dilated Cardiomyopathy and Obstructive Sleep Apnea
NCT03439514	PHASE3	TERMINATED	A Study of ARRY-371797 (PF-07265803) in Patients With Symptomatic Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation
NCT05237323	PHASE3	COMPLETED	Micophenolate Mofetil Versus Azathioprine in Myocarditis
NCT05849766	PHASE3	COMPLETED	Effect of Dapagliflozin on Cardiac Structure, Function and Secondary Mitral Regurgitation in Patients with Left Ventricle Dysfunction
NCT06250257	PHASE3	RECRUITING	Bromocriptine in Dilated Cardiomyopathy Among Women of Reproductive Age
NCT00629018	PHASE2	COMPLETED	Safety and Efficacy Study of Stem Cell Transplantation to Treat Dilated Cardiomyopathy
NCT00629096	PHASE2	COMPLETED	Intracoronary Infusion of Autologous Bone Marrow Cells for Treatment of Idiopathic Dilated Cardiomyopathy
NCT00765518	PHASE2	COMPLETED	Use of Ixmyelocel-T (Formerly Cardiac Repair Cell [CRC] Treatment) in Patients With Heart Failure Due to Dilated Cardiomyopathy (IMPACT-DCM)
NCT00847964	PHASE2	COMPLETED	Safety and Feasibility of Algisyl-LVR™ as a Method of Left Ventricular Restoration in Patients With DCM Undergoing Open-heart Surgery
NCT01020968	PHASE2	COMPLETED	Use of Ixmyelocel-T (Formerly Catheter-based Cardiac Repair Cell [CRC]) Treatment in Patients With Heart Failure Due to Dilated Cardiomyopathy
NCT01302171	PHASE2	COMPLETED	Bone Marrow Derived Adult Stem Cells for Dilated Cardiomyopathy
NCT01350310	PHASE2	COMPLETED	Safety and Efficacy Study of Intramyocardial Stem Cell Therapy in Patients With Dilated Cardiomyopathy
NCT02133911	PHASE2	COMPLETED	A Pilot Trial of Ranolazine to Treat Patients With Dilated Cardiomyopathy
NCT03071653	PHASE2	SUSPENDED	Left Cardiac Sympathetic Denervation for Cardiomyopathy Feasibility Pilot Study
NCT03572660	PHASE2	ACTIVE_NOT_RECRUITING	Use of Bone Marrow Derived Stem Cell and G-CSF With Circulatory Assistance in the Treatment of DCM
NCT03775070	PHASE2	COMPLETED	Simvastatin Therapy in Patients With Dilated Cardiomyopathy.
NCT04405804	PHASE2	UNKNOWN	Early Administration of Ivabradine in Children With Heart Failure
NCT05410873	PHASE2	COMPLETED	Examining the Effects of Mitochondrial Oxidative Stress in DCM
NCT06632834	PHASE2	RECRUITING	Outcome-targeted Therapy: Principle and Outcome Evaluation: Clinical Study and Phenotype-genotype Correlation
NCT00585546	PHASE1	TERMINATED	Harefield Recovery Protocol Study for Patients With Refractory Chronic Heart Failure
NCT02293603	PHASE1	UNKNOWN	Dilated cardiomYopathy iNtervention With Allogeneic MyocardIally-regenerative Cells (DYNAMIC)
NCT03062956	PHASE1	COMPLETED	A Single Ascending Dose Study Assessing the Safety, Tolerability, PK and PD of MYK-491
NCT03129568	PHASE1	COMPLETED	Transcoronary Infusion of Cardiac Progenitor Cells in Pediatric Dilated Cardiomyopathy
NCT04982081	PHASE1	UNKNOWN	Treating Congestive HF With hiPSC-CMs Through Endocardial Injection
NCT06381466	PHASE1	TERMINATED	A Study to Investigate Safety, Tolerability, and Pharmacokinetics of Oral AZD0233 Compared With Placebo in Healthy Adult Participants.
NCT06464588	PHASE1	RECRUITING	A Phase 1 Open-Label Study of the Safety of Intravenous Allogeneic Neonatal Mesenchymal Cells (nMSCs) in Young Adult (1A) and Pediatric (1B) Patients With Dilated Cardiomyopathy (DCM)
NCT06902896	PHASE1	COMPLETED	Safety and Efficacy of FAP iCDC in End-stage Dilated Cardiomyopathy
NCT07137338	PHASE1	RECRUITING	A Phase 1 AAV Gene Therapy Trial Evaluating Safety and Preliminary Efficacy of RP-A701 in Subjects With BAG3 Dilated Cardiomyopathy
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