GCG

Summary

GCG (glucagon, HGNC:4191) is a protein-coding gene on chromosome 2q24.2, encoding Pro-glucagon (P01275). Plays a key role in glucose metabolism and homeostasis.

The protein encoded by this gene is a proglucagon precursor that is cleaved into four distinct mature peptides. One of these, glucagon, is a pancreatic hormone that counteracts the glucose-lowering action of insulin by stimulating glycogenolysis and gluconeogenesis in the liver. In addition, glucagon promotes lipolysis and ketone body formation during prolonged fasting or stress. Glucagon secretion is stimulated by low blood glucose and inhibited by high glucose or insulin. Glucagon is a ligand for a specific G-protein linked receptor called glucagon receptor, which activates the Gs protein-adenylate cyclase-cAMP-protein kinase A signaling pathway to regulate carbohydrate and lipid metabolism. Two of the other peptides, glucagon-like peptide-1 and glucagon-like peptide-2, are produced by the intestinal L-cells and secreted in response to nutrient ingestion, where they function as important regulators of glucose metabolism and intestinal physiology. Glucagon-like peptide-1 enhances glucose-dependent insulin secretion, suppresses glucagon release, slows gastric emptying, and promotes satiety, making it a key incretin hormone for maintaining postprandial glucose levels. Glucagon-like peptide-2 primarily acts on the gut, promoting intestinal growth, enhancing nutrient absorption, and supporting mucosal integrity. Both peptides exert their effects through specific G-protein-coupled receptors, glucagon-like peptide-1 receptor and glucagon-like peptide-2 receptor, respectively, and analogs of glucagon-like peptide-1 are used clinically for the treatment of type 2 diabetes and obesity. The fourth peptide is similar to glicentin, an active enteroglucagon produced in the intestinal L-cells. This peptide is thought to have multiple roles in gastrointestinal physiology, including stimulating intestinal growth, modulating gut motility, and influencing the secretion of other gut hormones. Although its precise functions are less well-characterized than those of glucagon, glucagon-like peptide-1, or glucagon-like peptide-2, glicentin-like peptides may contribute to postprandial digestive processes and the coordination of nutrient absorption.

Source: NCBI Gene 2641 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 4 total
• Druggable target: yes
• MANE Select transcript: NM_002054

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4191
Approved symbol	GCG
Name	glucagon
Location	2q24.2
Locus type	gene with protein product
Status	Approved
Aliases	GLP1, GLP2, GRPP, GLP-1
Ensembl gene	ENSG00000115263
Ensembl biotype	protein_coding
OMIM	138030
Entrez	2641

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 retained_intron, 2 protein_coding

ENST00000375497, ENST00000418842, ENST00000483769, ENST00000492913, ENST00000497568

RefSeq mRNA: 1 — MANE Select: NM_002054 NM_002054

CCDS: CCDS46439

Canonical transcript exons

ENST00000418842 — 6 exons

Exon	Start	End
ENSE00000779527	162144027	162144170
ENSE00000779528	162145540	162145677
ENSE00001636967	162142882	162143370
ENSE00001835555	162152158	162152247
ENSE00003473685	162147353	162147514
ENSE00003540134	162149087	162149187

Expression profiles

Bgee: expression breadth ubiquitous, 132 present calls, max score 99.98.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 3.9178 / max 4620.9135, expressed in 23 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
31537	3.8831	20
31533	0.0103	2
31535	0.0065	1
31539	0.0061	4
31534	0.0056	2
31536	0.0043	1
31538	0.0018	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
type B pancreatic cell	CL:0000169	99.98	gold quality
islet of Langerhans	UBERON:0000006	99.86	gold quality
body of pancreas	UBERON:0001150	98.95	gold quality
pancreas	UBERON:0001264	98.60	gold quality
rectum	UBERON:0001052	98.40	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.16	gold quality
ileal mucosa	UBERON:0000331	95.06	gold quality
colonic mucosa	UBERON:0000317	94.10	gold quality
epithelial cell of pancreas	CL:0000083	92.73	gold quality
small intestine Peyer’s patch	UBERON:0003454	89.89	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.77	gold quality
mucosa of transverse colon	UBERON:0004991	87.09	gold quality
small intestine	UBERON:0002108	84.91	gold quality
colonic epithelium	UBERON:0000397	76.70	gold quality
transverse colon	UBERON:0001157	73.86	gold quality
intestine	UBERON:0000160	72.94	gold quality
jejunal mucosa	UBERON:0000399	71.73	gold quality
large intestine	UBERON:0000059	68.99	gold quality
pancreatic ductal cell	CL:0002079	67.86	silver quality
colon	UBERON:0001155	67.80	gold quality
vermiform appendix	UBERON:0001154	66.08	gold quality
caecum	UBERON:0001153	63.40	gold quality
gall bladder	UBERON:0002110	62.34	gold quality
duodenum	UBERON:0002114	62.06	gold quality
ganglionic eminence	UBERON:0004023	61.22	gold quality
jejunum	UBERON:0002115	57.60	gold quality
sigmoid colon	UBERON:0001159	56.71	gold quality
embryo	UBERON:0000922	55.85	gold quality
oocyte	CL:0000023	52.06	gold quality
frontal pole	UBERON:0002795	50.41	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ENAD-27	yes	350099.86
E-GEOD-81608	yes	338432.10
E-GEOD-83139	yes	307567.99
E-HCAD-31	yes	254102.11
E-MTAB-5061	yes	159721.56
E-GEOD-81547	yes	156591.69
E-GEOD-125970	yes	7.08
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AHR, ARX, CDX2, EGR1, FOS, FOXA1, FOXA2, FOXM1, FOXO1, GATA4, HNF4A, ISL1, JUN, MAF, MAFA, MAFB, MYT1, NEUROD1, NEUROG3, NFATC2, NKX6-1, PAX2, PAX4, PAX6, PDHX, PDX1, POU3F4, PPARG, SOX4, SOX9, TCF3, TCF7L2, THRA, ZGLP1

miRNA regulators (miRDB)

45 targeting GCG, 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-126-5P	100.00	72.71	3180
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-5700	99.64	69.88	2280
HSA-MIR-488-3P	99.61	68.79	1731
HSA-MIR-5003-5P	99.61	69.13	1624
HSA-MIR-6083	99.47	68.73	2393
HSA-MIR-330-3P	99.41	69.95	2521
HSA-MIR-8077	99.17	66.67	862

Literature-anchored findings (GeneRIF, showing 40)

• low secretion of GLP-1 in girls with obesity may seriously and negatively influence the course of this disease while low levels in girls with anorexia nervosa are beneficial and promote appetite (PMID:11972291)
• present in human colorectal adenocarcinomas and liver metastases (PMID:12174892)
• role of polarity at Asp198 in determining binding site for glucagon-like peptide-1 receptor (PMID:12387900)
• There are interactions between this protein, specific NEFA and insulin secretion (PMID:12436337)
• some of the events that lead to the differentiation of pancreatic ductal cells in response to treatment with human GLP-1 (PMID:12459036)
• conclude that the elimination of GLP-1 is the same in obese type 2 diabetic petients and matched healthy subjects (PMID:12519856)
• The isolated N-terminal domain of the glucagon-like peptide-1 (GLP-1) receptor binds exendin peptides with much higher affinity than GLP-1. (PMID:12524435)
• leptin stimulates GLP-1 secretion from rodent and human intestinal L cells; leptin resistance may account for the decreased levels of GLP-1 found in obese humans (PMID:12540594)
• single treatment of sensitized mice with GLP diminishes both immediate and late-phase hypersensitivity reactions characteristic of food allergy by inhibiting transepithelial uptake of antigen (PMID:12736145)
• role of M1 and M2 muscarinic receptors expressed by human L cells in the control of GLP-1 secretion. (PMID:12810581)
• GLP-1 improves function and inhibit apoptosis in freshly isolated human islets. (PMID:12960095)
• GLP-1 has to be present in blood to stimulate insluin or suppress glucagon. Human pancreatic beta cells do not appear to possess memory for insulinotropic stimuli. (PMID:14517773)
• GLP-2 may prove to be important in the attempt to optimize remnant intestinal function thereby eliminating the need for parenteral support in short bowel syndrome. (PMID:14608103)
• Review article focuses on the complex integrative mechanisms that regulate the secretion of GLP-1 and GLP-2 from intestinal L cells, including both direct and indirect regulation by ingested nutrients. (PMID:14719035)
• delayed elimination in renal insufficiency (PMID:14988249)
• In morbid obesity, accelerated inactivation of circulating GLP-1 could at least partially account for plasma peptide levels lower than normal, defective availability of such a satiety factor possibly contributing to eating behaviour abnormalities. (PMID:15002062)
• Increased GLP-1 levels, which lead to decreased food intake, may also contribute to the weight loss that is associated with the use of this drug in obese diabetics. (PMID:15111524)
• GLP-1 is a regulator of islet cell mass as well as a regulator of insulin secretory action [review] (PMID:15289644)
• GLP-1 and GLP-2 exhibit a diverse array of metabolic, proliferative and cytoprotective actions with important clinical implications for the treatment of diabetes and gastrointestinal disease–REVIEW (PMID:15533774)
• GLP-1 protects against myocardial infarction in the isolated and intact rat heart. (PMID:15616022)
• GLP-1, like insulin, stimulates glucose uptake in myocytes, and this involves activation of PI3K/PKB, p44/42 MAPKs, partially p70s6k, and possibly PKC (PMID:15664668)
• Review. Summarizes signaling properties of GLP-1 that may explain its ability to increase beta-cell mass, to increase pancreatic insulin secretory capacity, and to lower levels of blood glucose in type 2 diabetic subjects. (PMID:15671479)
• Results demonstrate that glucagon like peptide-1 is capable of preserving beta-cell function and protecting cells from apoptotic cell death. (PMID:15821104)
• in overweight/obese subjects, glucagon-like peptide 1 concentrations after weight loss were decreased compared with before weight loss, and nutrient-related stimulation was abolished (PMID:15897480)
• Reduced secretion or action of GLP-1 or GIP does not explain a relative reduced beta-cell responsiveness to glucose or the slightly elevated plasma glucose concentrations observed in young low birth weight men (PMID:15899957)
• The glucose-lowering effect of GLP-1 is markedly reduced when the deceleration of gastric emptying is antagonized, illustrating the importance of this facet of the multiple antidiabetic actions of GLP-1. (PMID:15983224)
• important role for the irregularities in glucagon response in the postprandial glucose excursion in glucose intolerance and type 2 diabetes (PMID:16125528)
• Glucagon inhibits ghrelin secretion in humans. (PMID:16131602)
• GLP-1 has the potential to improve both alpha cell and beta cell function, and could be of benefit in patients with a broad range of metabolic disorders. (review) (PMID:16132964)
• GLP-1 is preserved in type 2 diabetic patients, this peptide was a candidate as a therapeutic agent for this disease. (review) (PMID:16142014)
• GLP-1 may be another important determiner of pancreatic endocrine differentiation as is pdx-1 (PMID:16153418)
• glicentin plays an important role in the regulating inhibition of the contraction reaction in normal human jejunum via NANC nerves, and has a direct action on the jejunal muscle receptor. (PMID:16201096)
• GLP-1 suppresses glucagon secretion, promotes satiety, delays gastric emptying and stimulates peripheral glucose uptake. Because of its multiple actions, GLP-1 is an attractive therapeutic target for the treatment of type 2 diabetes[review] (PMID:16202636)
• The body adapts to insulin resistance by increasing the glucagon response to arginine and by increasing the suppression of glucagon levels by glucose. (PMID:16362283)
• GLP-2 reduces gastric acid secretion but does not seem to have an influence on gastric emptying (PMID:16401467)
• the effects of intraduodenal fatty acids on ghrelin, PYY and GLP-2 secretion are dependent on their chain length (PMID:16563563)
• From 7 weeks of gestation, pancreatic duct epithelial cells begin to differentiate into insulin, glucagon and somatostatin-positive cells. (PMID:16736556)
• Glucagon suppression of ghrelin secretion is exerted at the hypothalamus-pituitary level. (PMID:16787987)
• Review summarizes the appetite suppressing effects of GLP-1 in the regulation of food intake, focusing on whether it is a true endocrine factor that acts as a physiologic, hormonal regulator of appetite. (PMID:16828127)
• Activin A has opposite effects on glucagon and arx gene expression in alpha-cells compared with beta-cells, a finding that may have relevance during pancreatic endocrine lineage specification and physiological function of the adult islets (PMID:16988001)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	gcgb	ENSDARG00000040907
danio_rerio	gcga	ENSDARG00000079296
mus_musculus	Gcg	ENSMUSG00000000394
rattus_norvegicus	Gcg	ENSRNOG00000005498

Protein

Protein identifiers

Pro-glucagon — P01275 (reviewed: P01275)

All UniProt accessions (1): P01275

UniProt curated annotations — full annotation on UniProt →

Function. Plays a key role in glucose metabolism and homeostasis. Regulates blood glucose by increasing gluconeogenesis and decreasing glycolysis. A counterregulatory hormone of insulin, raises plasma glucose levels in response to insulin-induced hypoglycemia. Plays an important role in initiating and maintaining hyperglycemic conditions in diabetes. Binds to and activates the glucagon receptor GCGR, which couples to the G(s) G protein and elevates intracellular cAMP, triggering downstream metabolic responses. Potent stimulator of glucose-dependent insulin release. Also stimulates insulin release in response to IL6. Plays important roles on gastric motility and the suppression of plasma glucagon levels. May be involved in the suppression of satiety and stimulation of glucose disposal in peripheral tissues, independent of the actions of insulin. Has growth-promoting activities on intestinal epithelium. May also regulate the hypothalamic pituitary axis (HPA) via effects on LH, TSH, CRH, oxytocin, and vasopressin secretion. Increases islet mass through stimulation of islet neogenesis and pancreatic beta cell proliferation. Inhibits beta cell apoptosis. Stimulates intestinal growth and up-regulates villus height in the small intestine, concomitant with increased crypt cell proliferation and decreased enterocyte apoptosis. The gastrointestinal tract, from the stomach to the colon is the principal target for GLP-2 action. Plays a key role in nutrient homeostasis, enhancing nutrient assimilation through enhanced gastrointestinal function, as well as increasing nutrient disposal. Stimulates intestinal glucose transport and decreases mucosal permeability. Significantly reduces food intake. Inhibits gastric emptying in humans. Suppression of gastric emptying may lead to increased gastric distension, which may contribute to satiety by causing a sensation of fullness. May modulate gastric acid secretion and the gastro-pyloro-duodenal activity. May play an important role in intestinal mucosal growth in the early period of life.

Subunit / interactions. Interacts with GCGR.

Subcellular location. Secreted Secreted.

Tissue specificity. Secreted in the A cells of the islets of Langerhans. Secreted in the A cells of the islets of Langerhans. Secreted from enteroendocrine L cells throughout the gastrointestinal tract. Also secreted in selected neurons in the brain. Secreted from enteroendocrine cells throughout the gastrointestinal tract. Also secreted in selected neurons in the brain. Secreted from enteroendocrine cells throughout the gastrointestinal tract. Secreted from enteroendocrine cells throughout the gastrointestinal tract.

Post-translational modifications. Proglucagon is post-translationally processed in a tissue-specific manner in pancreatic A cells and intestinal L cells. In pancreatic A cells, the major bioactive hormone is glucagon cleaved by PCSK2/PC2. In the intestinal L cells PCSK1/PC1 liberates GLP-1, GLP-2, glicentin and oxyntomodulin. GLP-1 is further N-terminally truncated by post-translational processing in the intestinal L cells resulting in GLP-1(7-37) GLP-1-(7-36)amide. The C-terminal amidation is neither important for the metabolism of GLP-1 nor for its effects on the endocrine pancreas.

Induction. Release is stimulated by hypoglycemia and inhibited by hyperglycemia, insulin, and somatostatin. Production by islet alpha cell is increased by IL6. Induced in response to nutrient ingestion.

Miscellaneous. In the glucagon antagonist, His-53 and Phe-58 are missing. This antagonist has been successfully utilized to reduce glucose concentration in vivo.

Similarity. Belongs to the glucagon family.

RefSeq proteins (1): NP_002045* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000532	Glucagon_GIP_secretin_VIP	Domain
IPR015550	Glucagon	Family

Pfam: PF00123

UniProt features (30 total): peptide 8, site 6, modified residue 6, helix 4, propeptide 2, signal peptide 1, region of interest 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

42 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
6PHI	X-RAY DIFFRACTION	1.1
6PHK	X-RAY DIFFRACTION	1.18
8ANK	X-RAY DIFFRACTION	1.3
6PHO	X-RAY DIFFRACTION	1.42
6PHL	X-RAY DIFFRACTION	1.44
8ANJ	X-RAY DIFFRACTION	1.55
6PHP	X-RAY DIFFRACTION	1.65
4ZGM	X-RAY DIFFRACTION	1.8
5OTU	X-RAY DIFFRACTION	1.8
6PHJ	X-RAY DIFFRACTION	1.99
5OTV	X-RAY DIFFRACTION	2
5OTX	X-RAY DIFFRACTION	2
3IOL	X-RAY DIFFRACTION	2.1
5OTW	X-RAY DIFFRACTION	2.1
6X18	ELECTRON MICROSCOPY	2.1
9N0E	ELECTRON MICROSCOPY	2.3
2G49	X-RAY DIFFRACTION	2.5
7DUQ	ELECTRON MICROSCOPY	2.5
7KI0	ELECTRON MICROSCOPY	2.5
7KI1	ELECTRON MICROSCOPY	2.5
9X22	ELECTRON MICROSCOPY	2.92
1BH0	X-RAY DIFFRACTION	3
5YQZ	X-RAY DIFFRACTION	3
7D68	ELECTRON MICROSCOPY	3
9IVG	ELECTRON MICROSCOPY	3
9X20	ELECTRON MICROSCOPY	3.18
6EDS	X-RAY DIFFRACTION	3.18
6VCB	ELECTRON MICROSCOPY	3.3
8JRV	ELECTRON MICROSCOPY	3.3
9E2A	ELECTRON MICROSCOPY	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P01275-F1	69.13	0.17

Antibody-complex structures (SAbDab): 11 — 5VAI, 6LMK, 6LML, 6VCB, 6X18, 7D68, 7DUQ, 7KI0, 7KI1, 9E2A, 9IVG

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 (6): 52–53 (cleavage; by pcsk2); 83–84 (cleavage; by pcsk1 and pcsk2); 91–92 (cleavage; by pcsk1); 97–98 (cleavage; by pcsk1); 130–131 (cleavage; by pcsk1); 145–146 (cleavage; by pcsk1)

Post-translational modifications (6): 54, 105, 108, 127, 150, 152

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-163359	Glucagon signaling in metabolic regulation
R-HSA-381676	Glucagon-like Peptide-1 (GLP1) regulates insulin secretion
R-HSA-381771	Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1)
R-HSA-416476	G alpha (q) signalling events
R-HSA-418555	G alpha (s) signalling events
R-HSA-420092	Glucagon-type ligand receptors
R-HSA-422085	Synthesis, secretion, and deacylation of Ghrelin

MSigDB gene sets: 214 (showing top): GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_TRANSPORT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, REACTOME_GLUCAGON_TYPE_LIGAND_RECEPTORS, GOBP_BEHAVIOR, GOCC_SECRETORY_GRANULE, GOBP_INSULIN_SECRETION, HOEGERKORP_CD44_TARGETS_TEMPORAL_DN, GOBP_CELLULAR_RESPONSE_TO_CARBOHYDRATE_STIMULUS, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_HORMONE_TRANSPORT, REACTOME_GLUCAGON_SIGNALING_IN_METABOLIC_REGULATION, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP

GO Biological Process (17): gluconeogenesis (GO:0006094), G protein-coupled receptor signaling pathway (GO:0007186), adenylate cyclase-modulating G protein-coupled receptor signaling pathway (GO:0007188), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), feeding behavior (GO:0007631), obsolete protein kinase A signaling (GO:0010737), response to activity (GO:0014823), positive regulation of insulin secretion (GO:0032024), positive regulation of insulin secretion involved in cellular response to glucose stimulus (GO:0035774), glucose homeostasis (GO:0042593), negative regulation of apoptotic process (GO:0043066), positive regulation of gluconeogenesis (GO:0045722), regulation of insulin secretion (GO:0050796), positive regulation of ERK1 and ERK2 cascade (GO:0070374), cellular response to glucagon stimulus (GO:0071377), positive regulation of calcium ion import (GO:0090280), negative regulation of execution phase of apoptosis (GO:1900118)

GO Molecular Function (6): signaling receptor binding (GO:0005102), hormone activity (GO:0005179), glucagon receptor binding (GO:0031769), identical protein binding (GO:0042802), receptor ligand activity (GO:0048018), protein binding (GO:0005515)

GO Cellular Component (6): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), endoplasmic reticulum lumen (GO:0005788), plasma membrane (GO:0005886), secretory granule lumen (GO:0034774), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
GPCR downstream signalling	2
Integration of energy metabolism	1
Regulation of insulin secretion	1
Incretin synthesis, secretion, and inactivation	1
Class B/2 (Secretin family receptors)	1
Peptide hormone metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signal transduction	2
insulin secretion	2
protein binding	2
cellular anatomical structure	2
glucose metabolic process	1
hexose biosynthetic process	1
G protein-coupled receptor activity	1
adenylate cyclase activity	1
G protein-coupled receptor signaling pathway	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	1
behavior	1
response to stimulus	1
positive regulation of protein secretion	1
regulation of insulin secretion	1
positive regulation of peptide hormone secretion	1
positive regulation of insulin secretion	1
insulin secretion involved in cellular response to glucose stimulus	1
regulation of insulin secretion involved in cellular response to glucose stimulus	1
carbohydrate homeostasis	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
gluconeogenesis	1
regulation of gluconeogenesis	1
positive regulation of biosynthetic process	1
positive regulation of glucose metabolic process	1
regulation of protein secretion	1
regulation of peptide hormone secretion	1
positive regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
regulation of ERK1 and ERK2 cascade	1
response to glucagon	1
cellular response to peptide hormone stimulus	1
positive regulation of calcium ion transport	1
calcium ion import	1
regulation of calcium ion import	1
negative regulation of apoptotic process	1
execution phase of apoptosis	1
regulation of execution phase of apoptosis	1

Protein interactions and networks

STRING

3924 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GCG	GLP1R	P43220	999
GCG	GCGR	P47871	999
GCG	INS	P01308	997
GCG	GIPR	P48546	993
GCG	SST	P01166	982
GCG	GLP2R	O95838	973
GCG	SCT	P09683	970
GCG	GIP	P09681	970
GCG	PPY	P01298	970
GCG	DPP4	P27487	947
GCG	GAST	P01350	935
GCG	IAPP	P10997	933
GCG	PYY	P10082	916
GCG	LEP	P41159	910
GCG	GHRH	P01286	905

IntAct

24 interactions, top by confidence:

A	B	Type	Score
IDE	GCG	psi-mi:“MI:0407”(direct interaction)	0.620
IDE	GCG	psi-mi:“MI:0570”(protein cleavage)	0.620
GCG	GCG	psi-mi:“MI:0407”(direct interaction)	0.600
GIPR	GCG	psi-mi:“MI:0407”(direct interaction)	0.560
NDUFB8	NDUFS4	psi-mi:“MI:0914”(association)	0.530
GCG	FAP	psi-mi:“MI:0194”(cleavage reaction)	0.440
DPP4	GCG	psi-mi:“MI:0194”(cleavage reaction)	0.440
GCG	DPP4	psi-mi:“MI:0194”(cleavage reaction)	0.440
FAP	GCG	psi-mi:“MI:0194”(cleavage reaction)	0.440
NUP62CL	WASH3P	psi-mi:“MI:0914”(association)	0.350
GCG	ZZEF1	psi-mi:“MI:0914”(association)	0.350
GCG	VGF	psi-mi:“MI:0914”(association)	0.350
GCG	METAP2	psi-mi:“MI:0914”(association)	0.350
GCG	INS	psi-mi:“MI:0403”(colocalization)	0.270

BioGRID (275): Atp7a (Affinity Capture-MS), G3bp2 (Affinity Capture-MS), Hnrnpa1 (Affinity Capture-MS), Npm1 (Affinity Capture-MS), Fkbp4 (Affinity Capture-MS), Pkm (Affinity Capture-MS), Hpcal1 (Affinity Capture-MS), Atp5b (Affinity Capture-MS), Ppia (Affinity Capture-MS), Hnrnpa2b1 (Affinity Capture-MS), Hspd1 (Affinity Capture-MS), Pdia3 (Affinity Capture-MS), Pgk1-rs7 (Affinity Capture-MS), Hspa2 (Affinity Capture-MS), Rps27a (Affinity Capture-MS)

ESM2 similar proteins: A0A023VZR2, A0A023W0B6, A0A023W0C3, A0A023W0V9, A0A023W0W9, A0A023W157, A0A023W163, A0A023W168, A0A3G1VU73, A0A3G1VU81, B5LUR0, B6E465, B9WZ56, E2AIS8, G7NYP9, O12956, O42143, O42144, P01273, P01275, P06308, P06883, P0DQF5, P10552, P17686, P19802, P21259, P22890, P29794, P41870, P41876, P42565, P50175, P61365, P61366, P68259, P84707, P91889, Q07981, Q1ELU7

Diamond homologs: C0HJJ2, C0HJJ3, C0HJJ4, C0HJJ5, C0HJJ6, C6EVG1, O12956, O42143, O42144, P01272, P01273, P01274, P01275, P01278, P04092, P04093, P05110, P06883, P07449, P09566, P09567, P09682, P09686, P09687, P0C235, P13189, P15438, P18108, P20394, P22890, P26349, P29794, P31297, P33528, P55095, P63294, P63295, P68259, P68260, P68273

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
GCG	up-regulates	GCGR	binding
GCG	up-regulates	LATS1
GCG	up-regulates	LATS2
PDHX	“down-regulates quantity by repression”	GCG	“transcriptional regulation”
PAX6	“up-regulates quantity by expression”	GCG	“transcriptional regulation”
GCG	up-regulates	LATS1/2
GCG	up-regulates	GLP1R	binding
CDX2/PAX6/P300	“up-regulates quantity by expression”	GCG	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	2
Likely benign	0
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

516 predictions. Top by Δscore:

Variant	Effect	Δscore
2:162144022:GTCA:G	donor_loss	1.0000
2:162144023:TCAC:T	donor_loss	1.0000
2:162144024:CACCT:C	donor_loss	1.0000
2:162144025:A:AG	donor_loss	1.0000
2:162144026:CC:C	donor_loss	1.0000
2:162144166:GGAAA:G	acceptor_gain	1.0000
2:162144167:GAAA:G	acceptor_gain	1.0000
2:162144168:AAA:A	acceptor_gain	1.0000
2:162144169:AA:A	acceptor_gain	1.0000
2:162144171:C:CC	acceptor_gain	1.0000
2:162145538:A:AC	donor_gain	1.0000
2:162145539:C:CG	donor_gain	1.0000
2:162145539:CT:C	donor_gain	1.0000
2:162145539:CTCT:C	donor_gain	1.0000
2:162145673:TATTC:T	acceptor_gain	1.0000
2:162145674:ATTC:A	acceptor_gain	1.0000
2:162145675:TTC:T	acceptor_gain	1.0000
2:162145676:TC:T	acceptor_gain	1.0000
2:162145677:CC:C	acceptor_gain	1.0000
2:162145678:C:CC	acceptor_gain	1.0000
2:162145678:CT:C	acceptor_loss	1.0000
2:162145679:T:G	acceptor_loss	1.0000
2:162147349:TTAC:T	donor_loss	1.0000
2:162147351:A:AC	donor_gain	1.0000
2:162147351:A:AG	donor_loss	1.0000
2:162147352:C:CC	donor_gain	1.0000
2:162147511:TGAT:T	acceptor_gain	1.0000
2:162144027:C:G	donor_loss	0.9900
2:162145531:CAGA:C	donor_gain	0.9900
2:162145534:A:AC	donor_gain	0.9900

AlphaMissense

1213 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:162145564:A:G	L123P	0.998
2:162145575:G:C	F119L	0.998
2:162145575:G:T	F119L	0.998
2:162145576:A:G	F119S	0.998
2:162145577:A:G	F119L	0.998
2:162147374:A:G	L78S	0.998
2:162147385:A:C	F74L	0.998
2:162147385:A:T	F74L	0.998
2:162147386:A:C	F74C	0.998
2:162147386:A:G	F74S	0.998
2:162147387:A:G	F74L	0.998
2:162147434:A:C	F58C	0.998
2:162145576:A:C	F119C	0.997
2:162147441:C:G	G56R	0.997
2:162145631:C:A	G101W	0.996
2:162147410:A:G	L66P	0.996
2:162147433:G:C	F58L	0.996
2:162147433:G:T	F58L	0.996
2:162147434:A:G	F58S	0.996
2:162147435:A:G	F58L	0.996
2:162147441:C:A	G56C	0.996
2:162145589:C:G	A115P	0.995
2:162145631:C:G	G101R	0.995
2:162145631:C:T	G101R	0.995
2:162145641:T:A	R97S	0.995
2:162145641:T:G	R97S	0.995
2:162147396:C:G	A71P	0.995
2:162147427:A:C	S60R	0.995
2:162147427:A:T	S60R	0.995
2:162147429:T:G	S60R	0.995

dbSNP variants (sampled 300 via entrez): RS1000055899 (2:162145215 C>A), RS1000075903 (2:162145436 A>G), RS1000516016 (2:162149292 A>G), RS1000569849 (2:162149654 T>A), RS1000942037 (2:162151545 A>G), RS1001564827 (2:162148321 T>C), RS1001620660 (2:162148256 G>A), RS1001979130 (2:162149998 G>A), RS1002209030 (2:162154203 C>G), RS1002367540 (2:162143971 A>C,G), RS1002515348 (2:162146670 A>G), RS1002566192 (2:162147033 G>C), RS1002751336 (2:162152449 A>C,T), RS1002804370 (2:162152976 G>C,T), RS1003184142 (2:162153285 T>C)

Disease associations

OMIM: gene MIM:138030 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006921_12	Regular attendance at a pub or social club	2.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009592	social interaction measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5736 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs13429709	Other	3	clozapine;olanzapine	Schizophrenia

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1990761	GCG		0.00	0
rs13429709	GCG	3	2.00	1	clozapine;olanzapine
rs41368446	GCG		0.00	0

Binding affinities (BindingDB)

108 measured of 108 human assays (108 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
3-[[4-[(3,3-dimethylcyclobutyl)-[[2-[4-(trifluoromethyl)pyrazol-1-yl]pyrimidin-5-yl]amino]methyl]benzoyl]amino]propanoic acid	KI	5.55 nM	US-8507533: Glucagon receptor modulators
3-[[4-[(S)-cyclohexyl-[[6-[4-(trifluoromethyl)pyrazol-1-yl]-3-pyridinyl]amino]methyl]benzoyl]amino]propanoic acid	KI	9.05 nM	US-8507533: Glucagon receptor modulators
3-[[4-[(3,3-dimethylcyclobutyl)-[(6-fluoro-3-methylquinolin-2-yl)amino]methyl]benzoyl]amino]propanoic acid	KI	14 nM	US-8927577: Quinolinyl glucagon receptor modulators
3-[[4-[(3,3-dimethylcyclobutyl)-[[6-[4-(trifluoromethyl)pyrazol-1-yl]-3-pyridinyl]amino]methyl]benzoyl]amino]propanoic acid	KI	15.8 nM	US-8507533: Glucagon receptor modulators
3-[[4-[cyclohexyl-[[6-[4-(trifluoromethyl)pyrazol-1-yl]-3-pyridinyl]amino]methyl]benzoyl]amino]propanoic acid	KI	17 nM	US-8507533: Glucagon receptor modulators
3-[[4-[cyclobutyl-[3,5-dimethyl-4-[4-(trifluoromethyl)pyrazol-1-yl]phenoxy]methyl]benzoyl]amino]propanoic acid	KI	20.2 nM	US-8507533: Glucagon receptor modulators
3-[[4-[(1S)-1-[[6-(4-tert-butylpyrazol-1-yl)-3-pyridinyl]amino]butyl]benzoyl]amino]propanoic acid	KI	20.2 nM	US-8507533: Glucagon receptor modulators
3-[[4-[(3,3-dimethylcyclobutyl)-[(7-fluoroquinolin-3-yl)amino]methyl]benzoyl]amino]propanoic acid	KI	25 nM	US-8927577: Quinolinyl glucagon receptor modulators
3-[[4-[1-[[6-(4-phenylpyrazol-1-yl)-3-pyridinyl]amino]butyl]benzoyl]amino]propanoic acid	KI	25.7 nM	US-8507533: Glucagon receptor modulators
3-[[4-[(R)-cyclohexyl-[[6-[4-(trifluoromethyl)pyrazol-1-yl]-3-pyridinyl]amino]methyl]benzoyl]amino]propanoic acid	KI	26.7 nM	US-8507533: Glucagon receptor modulators
3-[[6-[[(1R)-1-[3,5-dimethyl-4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]-3-methylbutyl]amino]pyridine-3-carbonyl]amino]propanoic acid	KI	27.4 nM	US-8507533: Glucagon receptor modulators
3-[[4-[1-[[6-(4-phenylimidazol-1-yl)-3-pyridinyl]amino]butyl]benzoyl]amino]propanoic acid	KI	29.3 nM	US-8507533: Glucagon receptor modulators
3-[[4-[(1R)-1-[[6-(4-tert-butylpyrazol-1-yl)-3-pyridinyl]amino]butyl]benzoyl]amino]propanoic acid	KI	30.2 nM	US-8507533: Glucagon receptor modulators
3-[[4-[1-[3-methoxy-5-methyl-4-[4-(trifluoromethyl)pyrazol-1-yl]phenoxy]butyl]benzoyl]amino]propanoic acid	KI	32.3 nM	US-8507533: Glucagon receptor modulators
3-[[4-[5-chloro-2-[[4-(2,4-dichlorophenyl)anilino]methyl]phenyl]benzoyl]amino]propanoic acid	KI	33 nM	US-9045389: Biphenyl derivatives useful as glucagon receptor antagonists
3-[[4-[(S)-(3,3-dimethylcyclobutyl)-[[6-[4-(trifluoromethyl)imidazol-1-yl]-3-pyridinyl]amino]methyl]benzoyl]amino]propanoic acid	KI	35 nM	US-8507533: Glucagon receptor modulators
3-[[4-[(3,3-dimethylcyclobutyl)-[3,5-dimethyl-4-[4-(trifluoromethyl)pyrazol-1-yl]phenoxy]methyl]benzoyl]amino]propanoic acid	KI	35.2 nM	US-8507533: Glucagon receptor modulators
3-[[4-[2-[[4-(4-fluoro-3-nitrophenyl)anilino]methyl]phenyl]benzoyl]amino]propanoic acid	KI	38 nM	US-9045389: Biphenyl derivatives useful as glucagon receptor antagonists
3-[[4-[1-[[2-[4-(trifluoromethyl)pyrazol-1-yl]pyrimidin-5-yl]amino]butyl]benzoyl]amino]propanoic acid	KI	38.2 nM	US-8507533: Glucagon receptor modulators
ethyl 3-[[4-[(3,3-dimethylcyclobutyl)-[[2-[4-(trifluoromethyl)pyrazol-1-yl]pyrimidin-5-yl]amino]methyl]benzoyl]amino]propanoate	KI	41 nM	US-8507533: Glucagon receptor modulators
3-[[4-[(3,3-dimethylcyclobutyl)-[[6-[4-(trifluoromethyl)imidazol-1-yl]-3-pyridinyl]amino]methyl]benzoyl]amino]propanoic acid	KI	42.2 nM	US-8507533: Glucagon receptor modulators
3-[[4-[cyclopentyl-[[2-[4-(trifluoromethyl)imidazol-1-yl]pyrimidin-5-yl]amino]methyl]benzoyl]amino]propanoic acid	KI	44.7 nM	US-8507533: Glucagon receptor modulators
3-[[4-[2-[[4-(4-chlorophenyl)anilino]methyl]phenyl]-3-methylbenzoyl]amino]propanoic acid	KI	45 nM	US-9045389: Biphenyl derivatives useful as glucagon receptor antagonists
3-[[4-[[[6-(4-tert-butylimidazol-1-yl)-3-pyridinyl]amino]-cyclopentylmethyl]benzoyl]amino]propanoic acid	KI	45.7 nM	US-8507533: Glucagon receptor modulators
3-[[4-[(1S)-1-(4-indazol-2-yl-3,5-dimethylphenoxy)butyl]benzoyl]amino]propanoic acid	KI	47.8 nM	US-8507533: Glucagon receptor modulators
3-[[4-[(3,3-dimethylcyclobutyl)-[(6-fluoroquinolin-3-yl)amino]methyl]benzoyl]amino]propanoic acid	KI	50 nM	US-8927577: Quinolinyl glucagon receptor modulators
3-[[4-[cyclopentyl-[3,5-dimethyl-4-[4-(trifluoromethyl)imidazol-1-yl]phenoxy]methyl]benzoyl]amino]propanoic acid	KI	51 nM	US-8507533: Glucagon receptor modulators
3-[[4-[(3,3-dimethylcyclobutyl)-[(3-methylquinolin-2-yl)amino]methyl]benzoyl]amino]propanoic acid	KI	53 nM	US-8927577: Quinolinyl glucagon receptor modulators
3-[[6-[(1S)-3-methyl-1-[[6-[4-(trifluoromethyl)pyrazol-1-yl]-3-pyridinyl]amino]butyl]pyridine-3-carbonyl]amino]propanoic acid	KI	57.4 nM	US-8507533: Glucagon receptor modulators
3-[[4-[1-[[6-(4-phenylpyrazol-1-yl)-3-pyridinyl]oxy]butyl]benzoyl]amino]propanoic acid	KI	58 nM	US-8507533: Glucagon receptor modulators
3-[[4-[2-[[4-(4-chlorophenyl)anilino]methyl]phenyl]benzoyl]amino]propanoic acid	KI	60 nM	US-9045389: Biphenyl derivatives useful as glucagon receptor antagonists
3-[[4-[1-[4-(4-cyclopropylpyrazol-1-yl)-3,5-dimethylphenoxy]butyl]benzoyl]amino]propanoic acid	KI	62.6 nM	US-8507533: Glucagon receptor modulators
3-[[4-[1-[4-(5-chloroindazol-2-yl)phenoxy]butyl]benzoyl]amino]propanoic acid	KI	62.8 nM	US-8507533: Glucagon receptor modulators
3-[[4-[[[6-(4-chloro-3-methylpyrazol-1-yl)-3-pyridinyl]amino]-cyclopentylmethyl]benzoyl]amino]propanoic acid	KI	65.9 nM	US-8507533: Glucagon receptor modulators
3-[[4-[3-methyl-1-[[5-methyl-6-[4-(trifluoromethyl)pyrazol-1-yl]-3-pyridinyl]amino]butyl]benzoyl]amino]propanoic acid	KI	69.8 nM	US-8507533: Glucagon receptor modulators
3-[[4-[2-cyclopropyl-1-[[6-[4-(trifluoromethyl)pyrazol-1-yl]-3-pyridinyl]amino]ethyl]benzoyl]amino]propanoic acid	KI	71.6 nM	US-8507533: Glucagon receptor modulators
3-[[4-[2,2-dimethyl-1-[[6-[4-(trifluoromethyl)imidazol-1-yl]-3-pyridinyl]amino]propyl]benzoyl]amino]propanoic acid	KI	87.2 nM	US-8507533: Glucagon receptor modulators
3-[[4-[cyclopentyl-[[6-(4-propan-2-ylimidazol-1-yl)-3-pyridinyl]amino]methyl]benzoyl]amino]propanoic acid	KI	88.4 nM	US-8507533: Glucagon receptor modulators
3-[[4-[1-[3,5-dimethyl-4-[4-(trifluoromethyl)imidazol-1-yl]phenoxy]butyl]benzoyl]amino]propanoic acid	KI	89.5 nM	US-8507533: Glucagon receptor modulators
3-[[4-[3-methyl-1-[[6-(trifluoromethyl)quinolin-2-yl]amino]butyl]benzoyl]amino]propanoic acid	KI	91 nM	US-8927577: Quinolinyl glucagon receptor modulators
3-[[4-[cyclobutyl-[[6-[4-(trifluoromethyl)pyrazol-1-yl]-3-pyridinyl]amino]methyl]benzoyl]amino]propanoic acid	KI	91.9 nM	US-8507533: Glucagon receptor modulators
3-[[4-[(3,3-dimethylcyclobutyl)-[2-[4-(trifluoromethyl)pyrazol-1-yl]pyrimidin-5-yl]oxymethyl]benzoyl]amino]propanoic acid	KI	94.9 nM	US-8507533: Glucagon receptor modulators
3-[[4-[1-[4-(7-methylindazol-2-yl)phenoxy]butyl]benzoyl]amino]propanoic acid	KI	98.2 nM	US-8507533: Glucagon receptor modulators
3-[[4-[1-[[6-(4-cyclopropylpyrazol-1-yl)-3-pyridinyl]amino]butyl]benzoyl]amino]propanoic acid	KI	101 nM	US-8507533: Glucagon receptor modulators
3-[[4-[3-methyl-1-[(3-methylquinolin-2-yl)amino]butyl]benzoyl]amino]propanoic acid	KI	101 nM	US-8927577: Quinolinyl glucagon receptor modulators
3-[[4-[cyclopentyl-(4-indazol-2-ylphenoxy)methyl]benzoyl]amino]propanoic acid	KI	103 nM	US-8507533: Glucagon receptor modulators
3-[[4-[1-(4-indazol-2-ylphenoxy)butyl]benzoyl]amino]propanoic acid	KI	109 nM	US-8507533: Glucagon receptor modulators
3-[[4-[1-(4-indazol-2-yl-3,5-dimethylphenoxy)butyl]benzoyl]amino]propanoic acid	KI	109 nM	US-8507533: Glucagon receptor modulators
3-[[4-[3-methyl-1-[(4-methylquinolin-3-yl)amino]butyl]benzoyl]amino]propanoic acid	KI	109 nM	US-8927577: Quinolinyl glucagon receptor modulators
3-[[4-[(R)-(3,3-dimethylcyclobutyl)-[[6-[4-(trifluoromethyl)imidazol-1-yl]-3-pyridinyl]amino]methyl]benzoyl]amino]propanoic acid	KI	110 nM	US-8507533: Glucagon receptor modulators

ChEMBL bioactivities

128 potent at pChembl≥5 of 128 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.26	Ki	5.55	nM	CHEMBL3617567
8.24	Ki	5.75	nM	CHEMBL3648156
8.12	Ki	7.6	nM	CHEMBL3648139
8.04	Ki	9.05	nM	CHEMBL3648191
7.85	Ki	14	nM	CHEMBL3617569
7.80	Ki	15.8	nM	CHEMBL3648139
7.77	Ki	17	nM	CHEMBL3648133
7.70	Ki	20.2	nM	CHEMBL3648188
7.70	Ki	20.2	nM	CHEMBL3648156
7.60	Ki	25	nM	CHEMBL3681967
7.59	Ki	25.7	nM	CHEMBL3648167
7.57	Ki	26.7	nM	CHEMBL3648192
7.56	Ki	27.4	nM	CHEMBL3648171
7.55	Ki	28	nM	CHEMBL3648173
7.54	Ki	29	nM	CHEMBL3648167
7.53	Ki	29.3	nM	CHEMBL3648151
7.52	Ki	30.2	nM	CHEMBL3648187
7.49	Ki	32.3	nM	CHEMBL3648164
7.48	Ki	33	nM	CHEMBL3617574
7.46	Ki	35	nM	CHEMBL3648186
7.45	Ki	35.2	nM	CHEMBL3648163
7.42	Ki	38.2	nM	CHEMBL2381823
7.42	Ki	38	nM	CHEMBL3673117
7.41	Ki	39	nM	CHEMBL3617569
7.39	Ki	41	nM	CHEMBL3648195
7.38	Ki	42.2	nM	CHEMBL3648181
7.35	Ki	44.7	nM	CHEMBL3648183
7.35	Ki	45	nM	CHEMBL3673116
7.34	Ki	45.7	nM	CHEMBL3648145
7.33	Ki	47.3	nM	CHEMBL3648151
7.32	Ki	47.8	nM	CHEMBL3648184
7.30	Ki	50	nM	CHEMBL3681968
7.29	Ki	51	nM	CHEMBL3648153
7.28	Ki	53	nM	CHEMBL3617568
7.24	Ki	57.4	nM	CHEMBL3648190
7.24	Ki	57.2	nM	CHEMBL3648137
7.24	Ki	58	nM	CHEMBL3648155
7.22	Ki	60	nM	CHEMBL3673123
7.20	Ki	62.8	nM	CHEMBL3648158
7.20	Ki	62.6	nM	CHEMBL3648160
7.18	Ki	65.9	nM	CHEMBL3648168
7.16	Ki	69.8	nM	CHEMBL3648134
7.14	Ki	71.6	nM	CHEMBL3648136
7.13	Ki	74	nM	CHEMBL3617568
7.12	Ki	76	nM	CHEMBL3681959
7.06	Ki	87.2	nM	CHEMBL3648176
7.05	Ki	88.4	nM	CHEMBL3648146
7.05	Ki	89.5	nM	CHEMBL3648159
7.04	Ki	91.9	nM	CHEMBL3648135
7.04	Ki	91	nM	CHEMBL3681963

PubChem BioAssay actives

6 with measured affinity, of 14 total; 6 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
4-[[(4-tert-butylcyclohexyl)-(5,6-dichloro-1-methylbenzimidazol-2-yl)amino]methyl]-N-(2H-tetrazol-5-yl)benzamide	343800: Binding affinity against human GLP1	ic50	3.7000	uM
4-[[(4-tert-butylcyclohexyl)-(5-cyclopentyloxy-1-methylbenzimidazol-2-yl)amino]methyl]-N-(2H-tetrazol-5-yl)benzamide	343800: Binding affinity against human GLP1	ic50	5.0000	uM
4-[[(4-tert-butylcyclohexyl)-(1-methyl-6-propoxybenzimidazol-2-yl)amino]methyl]-N-(2H-tetrazol-5-yl)benzamide	343800: Binding affinity against human GLP1	ic50	5.0000	uM
4-[[(4-tert-butylcyclohexyl)-(5-methoxy-1-methylbenzimidazol-2-yl)amino]methyl]-N-(2H-tetrazol-5-yl)benzamide	343800: Binding affinity against human GLP1	ic50	5.9000	uM
4-[[(4-tert-butylcyclohexyl)-[1-methyl-5-(trifluoromethyl)benzimidazol-2-yl]amino]methyl]-N-(2H-tetrazol-5-yl)benzamide	343800: Binding affinity against human GLP1	ic50	6.8000	uM
4-[[(4-tert-butylcyclohexyl)-(5-ethoxy-1-methylbenzimidazol-2-yl)amino]methyl]-N-(2H-tetrazol-5-yl)benzamide	343800: Binding affinity against human GLP1	ic50	7.6000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Orlistat	decreases reaction, increases secretion, decreases expression, decreases secretion	3
geraniol	decreases reaction, increases secretion, increases reaction	1
osteum	decreases reaction, increases secretion	1
9-(tetrahydro-2-furyl)-adenine	increases secretion, decreases reaction	1
denatonium	decreases reaction, increases secretion, increases reaction	1
bicalutamide	decreases expression	1
CGP 52608	affects binding, increases reaction	1
SB 203580	decreases reaction, increases expression, increases secretion	1
dexloxiglumide	decreases reaction, increases secretion	1
citronellal	increases secretion	1
imeglimin	decreases secretion, decreases expression	1
Olive Oil	increases secretion, decreases reaction	1
Gatifloxacin	increases expression, decreases reaction, increases secretion	1
Cyclic AMP	affects binding, increases activity, increases chemical synthesis, increases reaction, affects localization	1
Adrenergic beta-Antagonists	decreases response to substance	1
Benzo(a)pyrene	affects methylation	1
Calcium Channel Blockers	decreases response to substance	1
Clofibrate	affects secretion	1
Diazoxide	decreases reaction, increases secretion	1
Dietary Fats	increases secretion, decreases reaction	1
Environmental Pollutants	increases secretion	1
Fatty Acids, Nonesterified	decreases abundance, decreases reaction, increases secretion	1
Glucose	decreases reaction, increases secretion, decreases abundance	1
Metoclopramide	increases secretion	1
Niacin	decreases abundance, decreases reaction, increases secretion	1
Pesticides	increases secretion, affects reaction	1
Tretinoin	increases expression	1
Valproic Acid	decreases methylation	1
Aflatoxin B1	decreases methylation	1
Chitosan	increases secretion, decreases reaction, increases expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3705314	Binding	Glucagon SPA Assay: The Glucagon SPA assay is used to determine the ability of test compounds to block the binding of glucagon-cex to the glucagon receptors.	Glucagon receptor modulators

Clinical trials (associated diseases)

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