HCAR2

Summary

HCAR2 (hydroxycarboxylic acid receptor 2, HGNC:24827) is a protein-coding gene on chromosome 12q24.31, encoding Hydroxycarboxylic acid receptor 2 (Q8TDS4). Acts as a high affinity receptor for both nicotinic acid (also known as niacin) and (D)-beta-hydroxybutyrate and mediates increased adiponectin secretion and decreased lipolysis through G(i)-protein-mediated inhibition of adenylyl cyclase.

Predicted to enable nicotinic acid receptor activity. Involved in neutrophil apoptotic process and positive regulation of neutrophil apoptotic process. Located in cell junction and plasma membrane.

Source: NCBI Gene 338442 — automated summary from GO annotations (Alliance of Genome Resources).

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 66 total
• GTEx eGene: eQTL in 20 tissues, sQTL in 0 (q < 0.05)
• Drug target: yes — 1 curated mechanism-of-action drug; 7 molecules with ChEMBL bioactivity
• Constraint (gnomAD): pLI 0.31 (intermediate), LOEUF 1.87 (unconstrained)
• MANE Select transcript: NM_177551
• Notable: 66 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24827
Approved symbol	HCAR2
Name	hydroxycarboxylic acid receptor 2
Location	12q24.31
Locus type	gene with protein product
Status	Approved
Aliases	HCA2, HM74A, PUMAG, Puma-g, NIACR1
Ensembl gene	ENSG00000182782
Ensembl biotype	protein_coding
OMIM	609163
Entrez	338442

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

MANE Select: ENST00000328880

ENST00000328880

RefSeq mRNA: 1 — MANE Select: NM_177551 NM_177551

CCDS: CCDS9235

Canonical transcript exons

ENST00000328880 — 1 exons

Exon	Start	End
ENSE00001294601	122701293	122703357

Expression profiles

Bgee: expression breadth ubiquitous, 122 present calls, max score 94.53.

FANTOM5 (CAGE): breadth broad, TPM avg 8.5947 / max 1582.7792, expressed in 329 samples.

Highest expression (Bgee): blood, lower esophagus mucosa, esophagus mucosa, olfactory segment of nasal mucosa, granulocyte.

Genetic regulation across tissues (GTEx eQTL / sQTL)

HCAR2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 20 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

20 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Esophagus Mucosa	eqtl	2.6e-38	-0.48	12:122697201:GT:G
Cells EBV-transformed lymphocytes	eqtl	1.0e-32	+0.75	12:122706828:T:C
Testis	eqtl	6.6e-29	-0.56	12:122701834:T:C
Prostate	eqtl	2.7e-06	-0.32	12:122686671:A:G
Adipose Subcutaneous	eqtl	2.8e-06	-0.13	12:122694983:A:G
Spleen	eqtl	1.2e-05	-0.42	12:122700991:G:T
Stomach	eqtl	1.1e-04	-0.30	12:122689119:T:TAAAC
Adipose Visceral Omentum	eqtl	5.5e-04	-0.16	12:122707907:C:T
Skin Sun Exposed Lower leg	eqtl	5.7e-04	+0.34	12:122742557:G:A
Cells Cultured fibroblasts	eqtl	6.3e-04	+0.25	12:122679515:G:C
Whole Blood	eqtl	7.4e-04	-0.09	12:122702063:G:A
Nerve Tibial	eqtl	9.5e-04	-0.19	12:122702049:C:A
Skin Not Sun Exposed Suprapubic	eqtl	2.1e-03	+0.25	12:122658070:G:A
Minor Salivary Gland	eqtl	3.5e-03	+0.27	12:122708997:A:C
Artery Tibial	eqtl	5.7e-03	-0.18	12:122682591:T:C
Colon Transverse	eqtl	1.1e-02	-0.27	12:122714845:C:A
Breast Mammary Tissue	eqtl	1.5e-02	-0.12	12:122682591:T:C
Brain Cortex	eqtl	3.1e-02	-0.31	12:122701054:G:A
Lung	eqtl	3.4e-02	-0.16	12:122693863:C:T
Vagina	eqtl	4.9e-02	-0.24	12:122718711:T:G

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
133839	8.5791	327
133838	0.0156	8

Top tissues by expression

showing 100 of 132 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
blood	UBERON:0000178	94.53	gold quality
lower esophagus mucosa	UBERON:0035834	91.98	gold quality
esophagus mucosa	UBERON:0002469	89.24	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	86.78	gold quality
granulocyte	CL:0000094	86.21	gold quality
skin of abdomen	UBERON:0001416	85.97	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.72	gold quality
zone of skin	UBERON:0000014	85.01	gold quality
skin of leg	UBERON:0001511	84.26	gold quality
spleen	UBERON:0002106	81.04	gold quality
bone marrow	UBERON:0002371	79.33	gold quality
minor salivary gland	UBERON:0001830	78.39	gold quality
omental fat pad	UBERON:0010414	78.17	gold quality
saliva-secreting gland	UBERON:0001044	77.46	gold quality
adipose tissue	UBERON:0001013	77.04	gold quality
leukocyte	CL:0000738	76.24	gold quality
subcutaneous adipose tissue	UBERON:0002190	75.79	gold quality
vagina	UBERON:0000996	75.65	gold quality
monocyte	CL:0000576	75.18	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	75.16	gold quality
vermiform appendix	UBERON:0001154	74.95	gold quality
placenta	UBERON:0001987	74.00	gold quality
bone marrow cell	CL:0002092	73.31	gold quality
thoracic mammary gland	UBERON:0005200	73.21	gold quality
upper lobe of left lung	UBERON:0008952	72.68	gold quality
tonsil	UBERON:0002372	72.21	gold quality
lung	UBERON:0002048	69.97	gold quality
right lung	UBERON:0002167	68.79	gold quality
esophagus	UBERON:0001043	66.10	gold quality
adult mammalian kidney	UBERON:0000082	64.56	gold quality
urinary bladder	UBERON:0001255	61.87	gold quality
duodenum	UBERON:0002114	60.58	gold quality
kidney	UBERON:0002113	60.57	gold quality
colonic epithelium	UBERON:0000397	60.45	gold quality
prostate gland	UBERON:0002367	59.88	gold quality
lymph node	UBERON:0000029	59.63	gold quality
cortex of kidney	UBERON:0001225	59.46	gold quality
gall bladder	UBERON:0002110	59.16	gold quality
liver	UBERON:0002107	58.61	gold quality
metanephros cortex	UBERON:0010533	58.39	gold quality
right lobe of liver	UBERON:0001114	57.65	gold quality
multicellular organism	UBERON:0000468	57.32	gold quality
fundus of stomach	UBERON:0001160	57.21	gold quality
left coronary artery	UBERON:0001626	56.30	gold quality
uterine cervix	UBERON:0000002	56.02	gold quality
body of stomach	UBERON:0001161	55.84	gold quality
ectocervix	UBERON:0012249	54.56	gold quality
left testis	UBERON:0004533	54.27	gold quality
stomach	UBERON:0000945	54.06	gold quality
smooth muscle tissue	UBERON:0001135	54.01	gold quality
testis	UBERON:0000473	53.84	gold quality
left uterine tube	UBERON:0001303	53.00	gold quality
hindlimb stylopod muscle	UBERON:0004252	52.51	gold quality
right testis	UBERON:0004534	52.30	gold quality
fallopian tube	UBERON:0003889	52.07	gold quality
apex of heart	UBERON:0002098	49.97	gold quality
heart	UBERON:0000948	49.35	gold quality
right atrium auricular region	UBERON:0006631	49.28	gold quality
transverse colon	UBERON:0001157	49.12	gold quality
muscle tissue	UBERON:0002385	48.57	gold quality
skeletal muscle tissue	UBERON:0001134	48.10	silver quality
rectum	UBERON:0001052	48.09	gold quality
heart left ventricle	UBERON:0002084	47.84	gold quality
tibial nerve	UBERON:0001323	47.80	gold quality
ascending aorta	UBERON:0001496	47.59	gold quality
endocervix	UBERON:0000458	47.25	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	47.08	gold quality
gastrocnemius	UBERON:0001388	47.05	gold quality
thoracic aorta	UBERON:0001515	46.92	gold quality
colon	UBERON:0001155	46.64	gold quality
left lobe of thyroid gland	UBERON:0001120	46.46	gold quality
right coronary artery	UBERON:0001625	46.35	gold quality
intestine	UBERON:0000160	46.29	gold quality
muscle of leg	UBERON:0001383	46.24	gold quality
thyroid gland	UBERON:0002046	46.10	gold quality
right lobe of thyroid gland	UBERON:0001119	45.21	gold quality
small intestine	UBERON:0002108	45.20	gold quality
descending thoracic aorta	UBERON:0002345	44.07	gold quality
endometrium	UBERON:0001295	44.05	gold quality
islet of Langerhans	UBERON:0000006	43.37	gold quality
tibial artery	UBERON:0007610	43.18	gold quality
popliteal artery	UBERON:0002250	43.17	gold quality
small intestine Peyer’s patch	UBERON:0003454	43.08	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	42.97	gold quality
myometrium	UBERON:0001296	42.16	gold quality
left adrenal gland cortex	UBERON:0035825	42.15	gold quality
substantia nigra	UBERON:0002038	41.75	gold quality
muscle layer of sigmoid colon	UBERON:0035805	41.58	gold quality
temporal lobe	UBERON:0001871	41.51	gold quality
amygdala	UBERON:0001876	41.34	gold quality
superior frontal gyrus	UBERON:0002661	41.08	silver quality
Ammon’s horn	UBERON:0001954	40.99	gold quality
putamen	UBERON:0001874	40.98	gold quality
anterior cingulate cortex	UBERON:0009835	40.93	gold quality
left adrenal gland	UBERON:0001234	40.69	gold quality
hypothalamus	UBERON:0001898	40.39	gold quality
adrenal gland	UBERON:0002369	40.34	gold quality
pituitary gland	UBERON:0000007	40.24	gold quality
caudate nucleus	UBERON:0001873	40.20	gold quality
pancreas	UBERON:0001264	40.11	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 63 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Spleen	tissue	24.4	medium
Esophagus	tissue	21.8	not detected
Bone marrow	tissue	20.9	medium
Adipose tissue	tissue	20.8	not detected
Skin 1	tissue	17.4	low
Vagina	tissue	13.8	low
Seminal vesicle	tissue	13.8	medium
Cerebral cortex	tissue	12.1	low
Lung	tissue	11.2	low
Thymus	tissue	9.8
Tonsil	tissue	9.5	medium
Appendix	tissue	9.3	low
Urinary bladder	tissue	6.5	medium
Parathyroid gland	tissue	5.1	not detected
Placenta	tissue	4.3	not detected
Breast	tissue	3.5	low
Liver	tissue	2.7	low
Pons	tissue	2.5
Salivary gland	tissue	2.1	low
Tongue	tissue	1.8
Testis	tissue	1.2	low
Prostate	tissue	1.1	not detected
Retrosplenial cortex	tissue	1.0
Small intestine	tissue	0.9	not detected
Duodenum	tissue	0.9	low
Gallbladder	tissue	0.8	low
Cervix	tissue	0.7	low
Fallopian tube	tissue	0.7	not detected
Lymph node	tissue	0.6	medium
Colon	tissue	0.6	low
Hippocampal formation	tissue	0.5
Stomach 1	tissue	0.4	not detected
Choroid plexus	tissue	0.4
Thalamus	tissue	0.4
Kidney	tissue	0.4	low
Pituitary gland	tissue	0.3
Heart muscle	tissue	0.3	low
Smooth muscle	tissue	0.3	not detected
Epididymis	tissue	0.3	low
Basal ganglia	tissue	0.3	low
Medulla oblongata	tissue	0.3
Hypothalamus	tissue	0.3
Adrenal gland	tissue	0.3	not detected
Retina	tissue	0.2
Rectum	tissue	0.2	not detected
Pancreas	tissue	0.2	not detected
Endometrium 1	tissue	0.2	not detected
Amygdala	tissue	0.2
Nucleus accumbens	tissue	0.2
Midbrain	tissue	0.2
Cerebellum	tissue	0.2	not detected
Hippocampus	tissue	0.2	low
Putamen	tissue	0.1
Substantia nigra	tissue	0.1
Thyroid gland	tissue	0.1	low
Locus coeruleus	tissue	0.1
Spinal cord	tissue	0.1
Postcentral gyrus	tissue	0.1
Occipital cortex	tissue	0.1
Ovary	tissue	0.0	low

Brain sub-regions (HPA Brain Atlas): detected in 173; highest nTPM — Area parastriata, superior (12.1), Ventrolateral tegmental area, A5 NE cell group (2.5), Blood vessel (1.7), Hippocampus, CA1 (0.5), Hippocampus, CA3 (0.5).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PPARG

miRNA regulators (miRDB)

Targeting HCAR2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

30 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-4756-3P	99.62	66.30	1319
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-6832-3P	99.52	70.44	1726
HSA-MIR-203A-3P	99.49	70.56	2806
HSA-MIR-6882-5P	99.35	71.13	1206
HSA-MIR-520A-5P	99.35	66.72	1632
HSA-MIR-525-5P	99.35	66.85	1615
HSA-MIR-146A-3P	99.13	68.99	1881
HSA-MIR-922	99.02	67.23	1838
HSA-MIR-4451	98.82	68.17	1455
HSA-MIR-6792-3P	98.41	66.86	1359
HSA-MIR-5088-3P	98.29	66.63	1310
HSA-MIR-665	97.60	65.64	1781
HSA-MIR-6856-3P	96.47	66.27	781
HSA-MIR-3927-5P	94.90	68.11	399

Functional genomics

gnomAD constraint: pLI 0.314, LOEUF 1.87, missense Z 1.69 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000328880 splits into 2 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
12:122,702,195–122,702,680	90 / 220.8	0.41	no
12:122,702,681–122,703,283	256 / 255.8	1.00	no

Literature-anchored findings (GeneRIF, showing 40)

• HM74b has high similarity to HM74 is a receptor for nicotinic acid [HM74b] (PMID:12646212)
• Our results provided direct evidence indicating that HM74A, but not HM74, was sufficient to mediate anti-lipolytic effect of niacin in adipose tissue. (PMID:16018973)
• However, the synergistic effects of HM74A were not dramatically affected by co-treatment with both inhibitors, indicating the cross-talk occurred at the receptor level. (PMID:16674924)
• neutrophils express functional GPR109A receptors,which might be involved in the regulation of neutrophil numbers (PMID:17932499)
• Data show that the high-affinity niacin receptor HM74A is significantly down-regulated in the anterior cingulate cortex of individuals with schizophrenia. (PMID:18639743)
• Data show that many phenolic acids, including those from the hydroxybenzoic and hydroxycinnamic acid classes, can bind and activate GPR109A (HM74a/PUMA-G), the receptor for the antidyslipidemic agent nicotinic acid. (PMID:19136666)
• GPR109A receptor plays an important role in the dual regulation of adiponectin secretion and lipolysis (PMID:19141678)
• Data show that the coordinated PPARgamma-mediated regulation of the GPR81, GPR109A and GPR109B presents a novel mechanism by which TZDs may reduce circulating free fatty acid levels and perhaps ameliorate insulin resistance in obese patients. (PMID:19633298)
• Data show that Mk-6892 was discovered as full and potent niacin receptor (GPR109A) agonist. (PMID:20184326)
• these results demonstrate that GPR109A and GPR109B dimerization is a constitutive process occurring early during biosynthesis. (PMID:20380810)
• The agonist-induced internalization of GPR109A receptors is regulated by GRK2 and arrestin3 in a pertussis toxin-sensitive manner and that internalized receptor recycling is independent of endosomal acidification. (PMID:20460384)
• niacin-mediated activation of GP109A in liver lowers ABCA1 expression leading to reduced hepatic cholesterol efflux to high density lipoprotein. (PMID:20655299)
• In contrast, in a squamous cell carcinoma derived cell line, both GPR109A and GPR109B show a more diffuse cellular localization and the receptors are nearly non-functional. (PMID:21655214)
• upon binding to niacin GPR109A receptors initially activate G(i), leading to dissociation of the Gbetagamma subunit from activated G(i), and subsequently induce ERK1/2 activation via two distinct pathways. (PMID:21768093)
• Nicotnic acid displays a range of effects that are lipoprotein-independent and potentially antiatherogenic. These effects are mediated by GPR109A. (PMID:22267479)
• A sequence from residues 329 to 343 in the C-terminal tail of HCA plays a crucial role in keeping HCA in an inactive conformation. (PMID:22962331)
• Review of the role of GPR109A and its downstream effects in the context of atherosclerosis and vascular inflammation, along with insights into strategy for future drug development. [Review Article] (PMID:23526298)
• despite NA’s anti-inflammatory effect on human macrophages, it has no effect on foam cells in reverse cholesterol transport; due to GPR109A down-regulation (PMID:23658787)
• These studies provide key insights into mechanisms by which GPR109A may influence cholesterol efflux in macrophages. (PMID:23770183)
• Although its functional role is still unknown, HCA2 may be potentially involved in the pathogenesis of various retinopathies and may offer a new therapeutic target. (PMID:24215154)
• GPR109A is a tumor suppressor in mammary gland. (PMID:24371223)
• the promiscuous activity exerted by niacin via both GPR109A and GPER may open new avenues towards a better understanding of the mechanisms involved in its biological action exerted in different pathophysiological conditions, including malignant diseases. (PMID:24662263)
• GPR109A expression is upregulated in blood and substantia nigra in Parkinson disease patients. (PMID:25329911)
• The results of this study suggested that GPR109A signaling is associated with T2DM, playing a role in regulation of the inflammatory cytokines. (PMID:25361930)
• These results suggest that the PKC pathway and PDGFR/EGFR transactivation pathway play important roles in HCA2-mediated Akt activation. (PMID:25375133)
• niacin, at a relatively low concentration, preserves the ability of HMVEC to form tubes under conditions of saturated fatty acid excess, and may elicit this effect through activation of GPR109A (PMID:25463108)
• Results suggest that the atypical motif asparaging-cysteine-systeine Asn(17)-Cys(18)-Cys(19) is crucial for the normal surface trafficking and function of hydroxycarboxylic acid receptor 2 protein hGPR109A. (PMID:25690651)
• new insights into the G protein coupling profiles of the HCA receptors and the function of the receptor’s C terminus (PMID:26656756)
• These results demonstrate that GPR109A is functionally expressed in both human and murine islet beta-cells. (PMID:27570060)
• GPR109A may inhibit inflammatory cytokine production, induced by palmitic acid, by MIN6 cells possibly via inhibiting the Akt/mTOR signaling pathway. (PMID:29263047)
• These results indicate that during aging, GPR109A modulates de novo lipid accumulation in liver and adipose tissue, and its dysregulation can lead to age-associated obesity and hepatic steatosis. (PMID:30659164)
• This review summarizes the use of niacin in treatment of dyslipidemia, the pharmacogenetics of niacin response and the potential role of HCAR2 signaling in the treatment of a variety of inflammatory and metabolic diseases. (PMID:31617441)
• C. butyricum decreased the fecal secondary BA contents, increased the cecal SCFA quantities, and activated G-protein coupled receptors (GPRs), such as GPR43 and GPR109A. The analysis of clinical specimens revealed that the expression of GPR43 and GPR109A gradually decreased from human normal colonic tissue to adenoma to carcinoma (PMID:31734354)
• Niacin Ameliorates Hepatic Steatosis by Inhibiting De Novo Lipogenesis Via a GPR109A-Mediated PKC-ERK1/2-AMPK Signaling Pathway in C57BL/6 Mice Fed a High-Fat Diet. (PMID:31858105)
• Hydroxycarboxylic Acid Receptor 2 Is a Zika Virus Restriction Factor That Can Be Induced by Zika Virus Infection Through the IRE1-XBP1 Pathway. (PMID:32039055)
• GPR Expression in Intestinal Biopsies From SCT Patients Is Upregulated in GvHD and Is Suppressed by Broad-Spectrum Antibiotics. (PMID:34777363)
• Rare and potentially pathogenic variants in hydroxycarboxylic acid receptor genes identified in breast cancer cases. (PMID:34852802)
• Ebola Virus Infection Induces HCAR2 Expression Leading to Cell Death. (PMID:37578011)
• Structural basis for ligand recognition and signaling of hydroxy-carboxylic acid receptor 2. (PMID:37932263)
• [GPR109A partly mediates inhibitory effects of beta-hydroxybutyric acid on lung adenocarcinoma cell proliferation, migration and invasion]. (PMID:37933650)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Hcar2	ENSMUSG00000045502
rattus_norvegicus	Hcar2	ENSRNOG00000071408

Paralogs (15): GPR31 (ENSG00000120436), GPR42 (ENSG00000126251), FFAR2 (ENSG00000126262), FFAR1 (ENSG00000126266), OXER1 (ENSG00000162881), OXGR1 (ENSG00000165621), P2RY1 (ENSG00000169860), P2RY6 (ENSG00000171631), GPR82 (ENSG00000171657), P2RY2 (ENSG00000175591), FFAR3 (ENSG00000185897), P2RY4 (ENSG00000186912), HCAR1 (ENSG00000196917), SUCNR1 (ENSG00000198829), HCAR3 (ENSG00000255398)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1933383) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 2 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal urinary bladder morphology	1
abnormal lipid homeostasis	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Meriones unguiculatus	Q99PE3	98.8%	Diamond
Bos taurus	P48042	96.8%	Diamond
Sus scrofa	Q5YA25	92.7%	Diamond
Apis mellifera	O61303	67.5%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
MIR9902-2	ncRNA	113218511
KNTC1	protein-coding	9735
MIR9902-1	ncRNA	113218484
HCAR1	protein-coding	27198
HCAR3	protein-coding	8843
RSRC2	protein-coding	65117
DENR	protein-coding	8562

Protein

Protein identifiers

Hydroxycarboxylic acid receptor 2 — Q8TDS4 (reviewed: Q8TDS4)

Alternative names: G protein-coupled receptor 109A, G protein-coupled receptor HM74A, Niacin receptor 1, Nicotinic acid receptor

All UniProt accessions (2): A0A4Y1JWQ0, Q8TDS4

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a high affinity receptor for both nicotinic acid (also known as niacin) and (D)-beta-hydroxybutyrate and mediates increased adiponectin secretion and decreased lipolysis through G(i)-protein-mediated inhibition of adenylyl cyclase. This pharmacological effect requires nicotinic acid doses that are much higher than those provided by a normal diet. Mediates nicotinic acid-induced apoptosis in mature neutrophils. Receptor activation by nicotinic acid results in reduced cAMP levels which may affect activity of cAMP-dependent protein kinase A and phosphorylation of target proteins, leading to neutrophil apoptosis. The rank order of potency for the displacement of nicotinic acid binding is 5-methyl pyrazole-3-carboxylic acid = pyridine-3-acetic acid > acifran > 5-methyl nicotinic acid = acipimox » nicotinuric acid = nicotinamide.

Subcellular location. Cell membrane.

Tissue specificity. Expression largely restricted to adipose tissue and spleen. Expressed on mature neutrophils but not on immature neutrophils or eosinophils.

Similarity. Belongs to the G protein-coupled receptor 1 family.

RefSeq proteins (1): NP_808219* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain
IPR051893	HCARs	Family

Pfam: PF00001

UniProt features (50 total): helix 16, topological domain 8, strand 8, transmembrane region 7, sequence variant 4, turn 3, chain 1, region of interest 1, modified residue 1, disulfide bond 1

Structure

Experimental structures (PDB)

showing 30 of 40 structures by resolution:

PDB	Title	Method	Resolution (Å)
8J6P	Cryo-EM structure of the MK-6892-bound human HCAR2-Gi1 complex	ELECTRON MICROSCOPY	2.55
8J6Q	Cryo-EM structure of the 3-HB and compound 9n-bound human HCAR2-Gi1 complex	ELECTRON MICROSCOPY	2.6
8JZ7	Cryo-EM structure of MK-6892-bound HCAR2 in complex with Gi protein	ELECTRON MICROSCOPY	2.6
9IZC	Cryo-EM structure of human HCAR2-Gi complex with MK1903	ELECTRON MICROSCOPY	2.68
8IJA	Cryo-EM structure of human HCAR2-Gi complex with niacin	ELECTRON MICROSCOPY	2.69
7ZL9	Crystal structure of human GPCR Niacin receptor (HCA2)	X-RAY DIFFRACTION	2.7
7ZLY	Crystal structure of human GPCR Niacin receptor (HCA2) expressed from Spodoptera …	X-RAY DIFFRACTION	2.7
9JKY	acifran-HCAR2-Gi complex	ELECTRON MICROSCOPY	2.72
9KT8	Cryo-EM structure of HCA2-Gi complex with acifran	ELECTRON MICROSCOPY	2.73
8J6R	Cryo-EM structure of the MK-6892-bound human HCAR2-Gi1 complex	ELECTRON MICROSCOPY	2.76
8I7V	Cryo-EM structure of Acipimox bound human hydroxy-carboxylic acid receptor 2 in complex …	ELECTRON MICROSCOPY	2.77
8J6J	Cryo-EM structure of thehydroxycarboxylic acid receptor 2-Gi protein complex bound with …	ELECTRON MICROSCOPY	2.8
9KT7	Cryo-EM structure of HCA2-Gi complex with MK6892	ELECTRON MICROSCOPY	2.8
8IHB	Cryo-EM structure of HCA2-Gi complex with GSK256073	ELECTRON MICROSCOPY	2.85
8JHY	Cryo-EM structure of compound 9n bound ketone body receptor HCAR2-Gi signaling complex	ELECTRON MICROSCOPY	2.87
9IQT	structure of niacin-HCA2-Gi	ELECTRON MICROSCOPY	2.9
8J6I	Cryo-EM structure of thehydroxycarboxylic acid receptor 2-Gi protein complex bound MK-6892	ELECTRON MICROSCOPY	2.92
8IHF	Cryo-EM structure of HCA2-Gi complex with MK6892	ELECTRON MICROSCOPY	2.97
8JIM	Cryo-EM structure of MMF bound ketone body receptor HCAR2-Gi signaling complex	ELECTRON MICROSCOPY	2.98
8H2G	Cryo-EM structure of niacin bound human hydroxy-carboxylic acid receptor 2 in complex …	ELECTRON MICROSCOPY	3.01
8J6L	Cryo-EM structure of thehydroxycarboxylic acid receptor 2-Gi protein complex bound niacin	ELECTRON MICROSCOPY	3.05
8IHH	Cryo-EM structure of HCA2-Gi complex with LUF6283	ELECTRON MICROSCOPY	3.06
9IZA	Cryo-EM structure of human HCAR2-Gi complex with SCH900271	ELECTRON MICROSCOPY	3.06
7XK2	Cryo-EM Structure of Human Niacin Receptor HCA2-Gi protein complex	ELECTRON MICROSCOPY	3.1
8IHI	Cryo-EM structure of HCA2-Gi complex with acifran	ELECTRON MICROSCOPY	3.11
8K5C	Cryo-EM structure of Acipimox bound human hydroxy-carboxylic acid receptor 2 (Local …	ELECTRON MICROSCOPY	3.13
8JII	Cryo-EM structure of compound 9n and niacin bound ketone body receptor HCAR2-Gi signaling …	ELECTRON MICROSCOPY	3.17
8IJB	Cryo-EM structure of human HCAR2-Gi complex with acipimox	ELECTRON MICROSCOPY	3.23
8UTD	CryoEM Structure of HCA2-Gi1 in complex with MK-1903	ELECTRON MICROSCOPY	3.24
8IJD	Cryo-EM structure of human HCAR2-Gi complex with MK-6892	ELECTRON MICROSCOPY	3.25

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TDS4-F1	83.13	0.58

Antibody-complex structures (SAbDab)

34 antibodies co-crystallized with this protein: 7XK2, 8H2G, 8I7V, 8I7W, 8IHB, 8IHF, 8IHH, 8IHI, 8IJ3, 8IJA, 8IJB, 8IJD, 8IY9, 8IYH, 8IYW, 8J6I, 8J6J, 8J6L, 8J6P, 8J6Q, 8J6R, 8JER, 8JHN, 8JHY, 8JII (+9 more)

Human Protein Atlas

Protein class: G-protein coupled receptors, GPCRs excl olfactory receptors, Predicted membrane proteins, GPCRHMM predicted membrane proteins, FDA approved drug targets, Small molecule drugs

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cell junctions

Antibody reliability (HPA): IH approved · IF supported

Functional residue map

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

Post-translational modifications (1)

Type	Positions
Phosphoserine	328

Disulfide bonds (1)

Type	Positions
Disulfide bond	100–177

Function

Pathways and Gene Ontology

Reactome pathways

3 curated (TAS) of 7; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

7 pathways:

ID	Pathway	Evidence
R-HSA-373076	Class A/1 (Rhodopsin-like receptors)	curated
R-HSA-418594	G alpha (i) signalling events	curated
R-HSA-3296197	Hydroxycarboxylic acid-binding receptors	curated
R-HSA-388396	GPCR downstream signalling	—
R-HSA-500792	GPCR ligand binding	—
R-HSA-162582	Signal Transduction	—
R-HSA-372790	Signaling by GPCR	—

MSigDB gene sets: 198 (showing top): GOBP_MYELOID_CELL_HOMEOSTASIS, GOBP_POSITIVE_REGULATION_OF_LEUKOCYTE_APOPTOTIC_PROCESS, GOBP_REGULATION_OF_LEUKOCYTE_APOPTOTIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_LIPID_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_HORMONE_TRANSPORT, FOXO4_01, FOXO1_01, GOBP_CELL_CELL_SIGNALING, MARTINEZ_RB1_TARGETS_UP, GOBP_REGULATION_OF_PROTEIN_SECRETION, GOBP_REGULATION_OF_LIPID_METABOLIC_PROCESS, GOBP_REGULATION_OF_CATABOLIC_PROCESS, HFH8_01

GO Biological Process (7): neutrophil apoptotic process (GO:0001781), G protein-coupled receptor signaling pathway (GO:0007186), positive regulation of neutrophil apoptotic process (GO:0033031), negative regulation of lipid catabolic process (GO:0050995), positive regulation of adiponectin secretion (GO:0070165), apoptotic process (GO:0006915), signal transduction (GO:0007165)

GO Molecular Function (3): nicotinic acid receptor activity (GO:0070553), G protein-coupled receptor activity (GO:0004930), protein binding (GO:0005515)

GO Cellular Component (3): plasma membrane (GO:0005886), cell junction (GO:0030054), membrane (GO:0016020)

Reactome top-level categories

5 top-level categories:

Category	Pathways
Signaling by GPCR	2
Class A/1 (Rhodopsin-like receptors)	1
GPCR ligand binding	1
GPCR downstream signalling	1
Signal Transduction	1

GO top-level categories

34 GO namespaces:

Category	Terms
G protein-coupled receptor activity	2
cellular anatomical structure	2
neutrophil homeostasis	1
inflammatory cell apoptotic process	1
myeloid cell apoptotic process	1
leukocyte apoptotic process	1
signal transduction	1
neutrophil apoptotic process	1
positive regulation of immune system process	1
regulation of neutrophil apoptotic process	1
positive regulation of myeloid cell apoptotic process	1
positive regulation of leukocyte apoptotic process	1
negative regulation of catabolic process	1
lipid catabolic process	1
negative regulation of lipid metabolic process	1
regulation of lipid catabolic process	1
positive regulation of hormone secretion	1
positive regulation of protein secretion	1
positive regulation of multicellular organismal process	1
adiponectin secretion	1
regulation of adiponectin secretion	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
transmembrane signaling receptor activity	1
G protein-coupled receptor signaling pathway	1
binding	1
membrane	1
cell periphery	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 4 of 13 annotations. The rest are phylogenetic / computational / electronic (IEA).

4 experimentally-supported GO terms:

GO term	NS	Evidence
neutrophil apoptotic process	BP	direct assay
positive regulation of neutrophil apoptotic process	BP	direct assay
cell junction	CC	direct assay
plasma membrane	CC	direct assay

Protein interactions and networks

STRING

showing 15 of 882 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HCAR2	DENR	O43583	827
HCAR2	SLC5A8	Q8N695	705
HCAR2	HDAC9	Q9UKV0	651
HCAR2	IL18	Q14116	595
HCAR2	PYY	P10082	575
HCAR2	OR51E1	Q8TCB6	566
HCAR2	IL10	P22301	553
HCAR2	SLC16A1	P53985	547
HCAR2	ALDH18A1	P54886	539
HCAR2	GPBAR1	Q8TDU6	535
HCAR2	GPR84	Q9NQS5	533
HCAR2	GCG	P01275	502
HCAR2	FOXP3	Q9BZS1	500
HCAR2	IL6	P05231	500
HCAR2	IL1B	P01584	498

IntAct

Human interaction partners of HCAR2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

3 partners by confidence:

Partner	Interaction type	MIscore	Records
RAMP1	physical association	0.400	2
RAMP2	physical association	0.400	2
RAMP3	physical association	0.400	2

SIGNOR signaling

6 signaling interactions:

A	Effect	B	Mechanism
HCAR2	“up-regulates activity”	GNAI2	binding
HCAR2	“up-regulates activity”	GNAZ	binding
HCAR2	“up-regulates activity”	GNAO1	binding
HCAR2	“up-regulates activity”	GNA13	binding
HCAR2	“up-regulates activity”	GNAI1	binding
“bis(2-ethylhexyl) phthalate”	“up-regulates activity”	HCAR2	“chemical activation”

Protein complexes (CORUM) (2)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

2 complexes by size:

Complex	Subunits	Members
★ HCAR2-HCAR3 complex	2	HCAR3, HCAR2
★ Hydroxycarboxylic acid receptor 2	1	HCAR2

Disease & clinical

Genetic variants

Variant evidence for HCAR2: 66 ClinVar records (0 pathogenic / likely pathogenic); 7 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	60
Likely benign	2
Benign	4

SpliceAI

Top 1 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 1 predictions of 1):

Position(s)	Effect	Δscore	Sites
12:122702361	acceptor_gain	0.2100

AlphaMissense

904 missense substitutions predicted likely pathogenic (of 2,431 scored), across 224 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D73	8	0.994	0.998
D290	8	0.979	0.995
N45	8	0.977	0.996
N110	8	0.952	0.993
F240	8	0.951	0.996
F117	8	0.947	0.980
N286	8	0.942	0.993
F244	8	0.939	0.998
D124	8	0.932	0.975
F52	8	0.925	0.982
F105	8	0.911	0.982
F301	8	0.876	0.972
D273	8	0.794	0.878
C100	7	0.984	0.992
C177	7	0.980	0.992
W93	7	0.975	0.996
R125	7	0.975	0.995
W152	7	0.973	0.998
C19	7	0.959	0.973
C266	7	0.958	0.978

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Head and Neck Squamous Cell Carcinoma)

Disease associations

OMIM: gene MIM:609163 | disease phenotypes:

GWAS associations

7 associations:

Study	Trait	p-value
GCST001465_19	Adiponectin levels	3e-10
GCST90002405_338	Reticulocyte count	2e-9
GCST006054_9	High altitude adaptation	6e-9
GCST009602_47	Metabolic syndrome	6e-9
GCST001463_7	Adiponectin levels	4e-6
GCST002233_6	Adiponectin levels	7e-6
GCST002935_28	Lead levels	9e-6

EFO canonical traits (from GWAS)

4 canonical traits:

EFO ID	Trait name
EFO:0004502	adiponectin measurement
EFO:0009105	high altitude adaptation
EFO:0000195	metabolic syndrome
EFO:0007986	reticulocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3785 (SINGLE PROTEIN)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the HCAR2 protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

1 curated-mechanism drugs:

Drug	Modality	Max phase
SCH-900271	Small molecule	2

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 400,795 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

7 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL345714	ACIPIMOX	4	7,126
CHEMBL2107333	DIMETHYL FUMARATE	4	23,217
CHEMBL589586	MONOMETHYL FUMARATE	4	11,661
CHEMBL573	NIACIN	4	355,192
CHEMBL397783	5-FLUORONICOTINIC ACID	3	390
CHEMBL2036958	SCH-900271	2	20
CHEMBL278488	ACIFRAN	2	3,189

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

1 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs2454727	niacin	Efficacy	Genotypes CT + TT is associated with decreased response to niacin as compared to genotype CC.	PMID:28628560

GtoPdb / IUPHAR curated pharmacology

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

Target class: gpcr — Hydroxycarboxylic acid receptors

Most potent curated ligand interactions (29 total), top 25:

Ligand	Action	Affinity	Parameter
SCH 900271	Agonist	8.7	pEC50
MK 6892	Full agonist	8.4	pKi
compound 21 [PMID: 21185185]	Full agonist	7.92	pIC50
compound 2g [PMID: 19309152]	Full agonist	7.89	pIC50
MK 1903	Full agonist	7.56	pEC50
GSK256073	Agonist	7.5	pEC50
compound 43 [PMID: 34781683]	Agonist	7.4	pEC50
Compound 780A	Agonist	7.4	pEC50
compound (+)17a [PMID: 20363624]	Full agonist	7.35	pEC50
(+)-5-(5-bromothiophen-3-yl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid	Full agonist	7.3	pEC50
[3H]nicotinic acid	Full agonist	7.3	pKd
Compound 245A	Agonist	7.2	pEC50
nicotinic acid	Full agonist	7.2	pEC50
5-butyl-1H-pyrazole-3-carboxylic acid	Partial agonist	7.1	pKi
compound 1q [PMID: 18029181]	Partial agonist	6.85	pIC50
compound 9n [PMID: 18752940]	Positive	6.77	pEC50
monomethyl fumarate	Full agonist	6.74	pKi
compound 8f [PMID: 20615702]	Full agonist	6.41	pIC50
acifran	Full agonist	5.9	pEC50
Compound 4a [PMID: 17452318]	Agonist	5.89	pIC50
MK 0354	Partial agonist	5.78	pEC50
acipimox	Full agonist	5.6	pEC50
compound 42 [PMID: 22420767]	Positive	5.59	pEC50
3-pyridine-acetic acid	Full agonist	5.3	pEC50
5-methyl nicotinic acid	Full agonist	5.1	pEC50

Binding affinities (BindingDB)

580 measured of 674 human assays (678 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
(S)-2-(2-amino-3-(3-(5-hydroxypyridin-2-yl)-1,2,4-oxadiazol-5-yl)propanamido)benzoic acid	IC50	1 nM
CHEMBL2036954	EC50	1 nM
2-(2,2,3,3-tetrafluoro-3-(3-(5-hydroxypyridin-2-yl)-1,2,4-oxadiazol-5-yl)propanamido)cyclohex-1-enecarboxylic acid	KI	1.4 nM
CHEMBL2036951	EC50	3 nM
CHEMBL2036948	EC50	4 nM
CHEMBL2036955	EC50	4 nM
CHEMBL2036950	EC50	5 nM
2-{3-[2-(2-chloro-4-hydroxyphenyl)-1,3-thiazol-5-yl]propanamido}benzoic acid	EC50	6 nM
(4S,5R)-2-(3-(3-(5-hydroxypyridin-2-yl)-1,2,4-oxadiazol-5-yl)propanamido)-4-methyl-5-(2,3,5-trifluorophenyl)cyclohex-1-enecarboxylic acid	EC50	6 nM
CHEMBL2036960	EC50	7 nM
2-{3-[5-(2-chloro-4-hydroxyphenyl)thiophen-2-yl]propanamido}benzoic acid	IC50	8 nM
CHEMBL4641579	IC50	8 nM
2-{3-[4-(5-hydroxypyridin-2-yl)phenyl]propanamido}benzoic acid	IC50	9 nM
CHEMBL4082765	EC50	9 nM
2-(3-(6-hydroxynaphthalen-2-yl)propanamido)-5-propylcyclohex-1-enecarboxylic acid	EC50	10 nM
CHEMBL2036952	EC50	10 nM
CHEMBL2036957	EC50	10 nM
2-(1-((3-(5-hydroxypyridin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)cyclopropanecarboxamido)cyclohex-1-enecarboxylic acid	KI	11 nM
5-(3,5-difluorophenyl)-2-(3-(6-hydroxynaphthalen-2-yl)propanamido)cyclohex-1-enecarboxylic acid	EC50	11 nM
CHEMBL2036828	EC50	11 nM
CHEMBL4164140	EC50	11 nM
CHEMBL2057618	EC50	12.9 nM
CHEMBL2036953	EC50	13 nM
CHEMBL2057610	EC50	14 nM
CHEMBL4647392	EC50	15 nM
CHEMBL2035002	EC50	16 nM
CHEMBL2036959	EC50	16 nM
2-(3-(3-(5-hydroxypyridin-2-yl)-1,2,4-oxadiazol-5-yl)propanamido)-5-propylcyclohex-1-enecarboxylic acid	EC50	17 nM
CHEMBL2036825	EC50	19 nM
2-{3-[2-(4-hydroxy-1H-pyrazol-1-yl)-1,3-thiazol-5-yl]propanamido}benzoic acid	IC50	20 nM
5-(2,3,5-trifluorophenyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxylic acid	IC50	20 nM
2-(3-(3-(5-hydroxypyridin-2-yl)-1,2,4-oxadiazol-5-yl)propanamido)cyclohex-1-enecarboxylic acid	EC50	21 nM
5-(3,5-difluorophenyl)-2-(3-(3-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-5-yl)propanamido)cyclohex-1-enecarboxylic acid	EC50	22 nM
CHEMBL1939047	EC50	22 nM
CHEMBL3589834	IC50	23 nM
2-(3-(3-(5-hydroxypyridin-2-yl)-1,2,4-oxadiazol-5-yl)-2-methylpropanamido)cyclohex-1-enecarboxylic acid	EC50	25 nM
2-{3-[2-(5-hydroxypyridin-2-yl)-1,3-thiazol-5-yl]propanamido}benzoic acid	IC50	26 nM
CHEMBL1939043	EC50	26 nM
CHEMBL2036823	EC50	26 nM
2-{3-[3-(5-hydroxypyridin-2-yl)-1,2,4-oxadiazol-5-yl]propanamido}benzoic acid	EC50	27 nM
5-(3-fluorophenyl)-2-(3-(3-(5-hydroxypyridin-2-yl)-1,2,4-oxadiazol-5-yl)propanamido)cyclohex-1-enecarboxylic acid	EC50	27 nM
CHEMBL2059221	EC50	27.5 nM
5-(3-fluorophenyl)-2-(3-(6-hydroxynaphthalen-2-yl)propanamido)cyclohex-1-enecarboxylic acid	EC50	28 nM
CHEMBL2036826	EC50	28 nM
CHEMBL2059827	EC50	28 nM
5-butyl-2-(3-(6-hydroxynaphthalen-2-yl)propanamido)cyclohex-1-enecarboxylic acid	EC50	30 nM
5-(2-fluorophenyl)-2-(3-(6-hydroxynaphthalen-2-yl)propanamido)cyclohex-1-enecarboxylic acid	EC50	31 nM
CHEMBL2036810	EC50	31 nM
2-(3-(3-chlorophenoxy)propoxy)pyrido[2,3-d]pyrimidin-4(3H)-one	IC50	33 nM
CHEMBL1939039	EC50	34 nM

ChEMBL bioactivities

903 potent at pChembl≥5 of 957 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.02	IC50	0.96	nM	MONOMETHYL FUMARATE
9.00	EC50	1	nM	CHEMBL2036954
9.00	IC50	1	nM	CHEMBL236162
9.00	IC50	1	nM	CHEMBL483336
9.00	IC50	1	nM	CHEMBL483337
9.00	IC50	1	nM	CHEMBL1770352
8.85	Ki	1.4	nM	CHEMBL1084657
8.70	EC50	2	nM	SCH-900271
8.52	EC50	3	nM	CHEMBL2036951
8.52	IC50	3	nM	CHEMBL520299
8.52	IC50	3	nM	CHEMBL483139
8.52	Ki	3	nM	CHEMBL1087302
8.52	IC50	3	nM	CHEMBL1083138
8.52	IC50	3	nM	CHEMBL1087302
8.40	EC50	4	nM	CHEMBL2036948
8.40	EC50	4	nM	CHEMBL2036955
8.40	IC50	4	nM	CHEMBL235256
8.40	IC50	4	nM	CHEMBL237248
8.40	IC50	4	nM	CHEMBL483353
8.40	IC50	4	nM	CHEMBL485196
8.40	Ki	4	nM	CHEMBL237248
8.40	Ki	4	nM	CHEMBL1086656
8.40	Ki	4	nM	CHEMBL1086657
8.40	IC50	4	nM	CHEMBL1087302
8.40	IC50	4	nM	CHEMBL1084576
8.40	IC50	4	nM	CHEMBL1770353
8.30	EC50	5	nM	CHEMBL2036950
8.30	IC50	5	nM	CHEMBL483352
8.30	IC50	5	nM	CHEMBL520513
8.30	IC50	5	nM	CHEMBL1085616
8.30	IC50	5	nM	CHEMBL1085156
8.30	IC50	5	nM	CHEMBL1770355
8.22	EC50	6	nM	CHEMBL236162
8.22	IC50	6	nM	CHEMBL483140
8.22	IC50	6	nM	CHEMBL1086354
8.22	IC50	6	nM	CHEMBL1084799
8.22	EC50	6	nM	CHEMBL1085589
8.22	IC50	6	nM	CHEMBL1086541
8.22	IC50	6	nM	CHEMBL237248
8.19	EC50	6.5	nM	CHEMBL483139
8.15	EC50	7	nM	CHEMBL2036960
8.15	IC50	7	nM	CHEMBL1084030
8.15	IC50	7	nM	CHEMBL1085148
8.13	EC50	7.4	nM	CHEMBL2057602
8.13	IC50	7.4	nM	CHEMBL1085414
8.10	IC50	8	nM	CHEMBL235954
8.10	IC50	8	nM	CHEMBL521326
8.10	Ki	8	nM	CHEMBL1086656
8.10	IC50	8	nM	CHEMBL482698
8.10	IC50	8	nM	CHEMBL1086353

PubChem BioAssay actives

929 with measured affinity, of 1852 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-[3-[2-(2-chloro-4-hydroxyphenyl)-1,3-thiazol-5-yl]propanoylamino]benzoic acid	1798331: Tritiated Niacin Binding Assay and [35S]-GTP-gammaS Binding Assay from Article 10.1021/jm700942d: “Discovery of biaryl anthranilides as full agonists for the high affinity niacin receptor.”	ic50	0.0010	uM
2-[[(2S)-2-amino-3-[3-(5-hydroxy-2-pyridinyl)-1,2,4-oxadiazol-5-yl]propanoyl]amino]benzoic acid	594510: Displacement of [3H]nicotinic acid from human GPR109A receptor	ic50	0.0010	uM
2-[3-(6-chloro-7-oxo-2H-benzo[g][1,2]benzoxazol-3-yl)propanoylamino]cyclohexene-1-carboxylic acid	353308: Displacement of [3H]niacin from human GPR109A expressed in CHO cells	ic50	0.0010	uM
2-[3-(7-hydroxypyrazolo[1,5-a]quinolin-3-yl)propanoylamino]cyclohexene-1-carboxylic acid	353308: Displacement of [3H]niacin from human GPR109A expressed in CHO cells	ic50	0.0010	uM
Monomethyl Fumarate	2038662: Agonist activity at Niacin receptor (unknown origin)	ic50	0.0010	uM
5-(2-cyclobutylethyl)-1H-pyrano[2,3-d]pyrimidine-2,4,7-trione	663584: Agonist activity at human recombinant GPR109a expressed in CHO cells assessed as inhibition of forskolin-induced cAMP accumulation	ec50	0.0010	uM
2-[[2,2,3,3-tetrafluoro-3-[3-(5-hydroxy-2-pyridinyl)-1,2,4-oxadiazol-5-yl]propanoyl]amino]cyclohexene-1-carboxylic acid	464646: Displacement of [3H]NA from cloned human GPR109A receptor expressed in CHO-K1 cells by spectrophotometry	ki	0.0014	uM
5-[3-(1-methylcyclopropyl)propyl]-1H-pyrano[2,3-d]pyrimidine-2,4,7-trione	663584: Agonist activity at human recombinant GPR109a expressed in CHO cells assessed as inhibition of forskolin-induced cAMP accumulation	ec50	0.0020	uM
2-[3-[3-(5-hydroxy-2-pyridinyl)-1,2,4-oxadiazol-5-yl]propanoylamino]cyclohexene-1-carboxylic acid	464646: Displacement of [3H]NA from cloned human GPR109A receptor expressed in CHO-K1 cells by spectrophotometry	ki	0.0030	uM
2-[3-(7-oxo-2H-benzo[g][1,2]benzoxazol-3-yl)propanoylamino]benzoic acid	353308: Displacement of [3H]niacin from human GPR109A expressed in CHO cells	ic50	0.0030	uM
2-[3-(7-oxo-2H-benzo[g][1,2]benzoxazol-3-yl)propanoylamino]cyclohexene-1-carboxylic acid	353308: Displacement of [3H]niacin from human GPR109A expressed in CHO cells	ic50	0.0030	uM
5-(3,5-difluorophenyl)-2-[3-(6-hydroxynaphthalen-2-yl)propanoylamino]cyclohexene-1-carboxylic acid	484757: Displacement of [3H]niacin from human niacin receptor expressed in CHO-KI cells	ic50	0.0030	uM
5-(4,4-difluorobutyl)-1H-pyrano[2,3-d]pyrimidine-2,4,7-trione	663584: Agonist activity at human recombinant GPR109a expressed in CHO cells assessed as inhibition of forskolin-induced cAMP accumulation	ec50	0.0030	uM
2-[3-[4-(2-chloro-4-hydroxyphenyl)phenyl]propanoylamino]benzoic acid	1798331: Tritiated Niacin Binding Assay and [35S]-GTP-gammaS Binding Assay from Article 10.1021/jm700942d: “Discovery of biaryl anthranilides as full agonists for the high affinity niacin receptor.”	ic50	0.0040	uM
2-[3-(7-hydroxy-4,5-dihydrobenzo[g][1,2]benzoxazol-3-yl)propanoylamino]cyclohexene-1-carboxylic acid	353308: Displacement of [3H]niacin from human GPR109A expressed in CHO cells	ic50	0.0040	uM
2-[[3-[3-(5-hydroxy-2-pyridinyl)-1,2,4-oxadiazol-5-yl]-2-methylpropanoyl]amino]cyclohexene-1-carboxylic acid	464646: Displacement of [3H]NA from cloned human GPR109A receptor expressed in CHO-K1 cells by spectrophotometry	ki	0.0040	uM
2-[[3-[3-(5-hydroxy-2-pyridinyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylpropanoyl]amino]cyclohexene-1-carboxylic acid	464646: Displacement of [3H]NA from cloned human GPR109A receptor expressed in CHO-K1 cells by spectrophotometry	ki	0.0040	uM
2-[3-(7-hydroxy-4,5-dihydrobenzo[g][1,2]benzoxazol-3-yl)propanoylamino]benzoic acid	353308: Displacement of [3H]niacin from human GPR109A expressed in CHO cells	ic50	0.0040	uM
2-[3-[3-(5-hydroxy-2-pyridinyl)-1,2,4-oxadiazol-5-yl]propanoylamino]benzoic acid	1798331: Tritiated Niacin Binding Assay and [35S]-GTP-gammaS Binding Assay from Article 10.1021/jm700942d: “Discovery of biaryl anthranilides as full agonists for the high affinity niacin receptor.”	ic50	0.0040	uM
2-[3-[3-(5-hydroxy-2-pyridinyl)-1,2,4-oxadiazol-5-yl]propanoylamino]-5-propylcyclohexene-1-carboxylic acid	484757: Displacement of [3H]niacin from human niacin receptor expressed in CHO-KI cells	ic50	0.0040	uM
2-[[(2R)-2-amino-3-[3-(5-hydroxy-2-pyridinyl)-1,2,4-oxadiazol-5-yl]propanoyl]amino]benzoic acid	594510: Displacement of [3H]nicotinic acid from human GPR109A receptor	ic50	0.0040	uM
5-(3-cyclopropylpropyl)-1H-pyrano[2,3-d]pyrimidine-2,4,7-trione	663584: Agonist activity at human recombinant GPR109a expressed in CHO cells assessed as inhibition of forskolin-induced cAMP accumulation	ec50	0.0040	uM
5-(3-methylbutyl)-1H-pyrano[2,3-d]pyrimidine-2,4,7-trione	663584: Agonist activity at human recombinant GPR109a expressed in CHO cells assessed as inhibition of forskolin-induced cAMP accumulation	ec50	0.0040	uM
2-[3-(7-oxo-1,2-dihydrobenzo[g]indazol-3-yl)propanoylamino]benzoic acid	353308: Displacement of [3H]niacin from human GPR109A expressed in CHO cells	ic50	0.0050	uM
2-[[(2S)-2-amino-3-[3-(5-hydroxy-2-pyridinyl)-1,2,4-oxadiazol-5-yl]propanoyl]amino]cyclohexene-1-carboxylic acid	594510: Displacement of [3H]nicotinic acid from human GPR109A receptor	ic50	0.0050	uM
5-(4-methylpentyl)-1H-pyrano[2,3-d]pyrimidine-2,4,7-trione	663584: Agonist activity at human recombinant GPR109a expressed in CHO cells assessed as inhibition of forskolin-induced cAMP accumulation	ec50	0.0050	uM
2-[3-(6-hydroxyimidazo[2,1-b][1,3]benzothiazol-2-yl)propanoylamino]cyclohexene-1-carboxylic acid	353308: Displacement of [3H]niacin from human GPR109A expressed in CHO cells	ic50	0.0050	uM
2-[3-[1-(5-hydroxy-2-pyridinyl)pyrazol-3-yl]propanoylamino]cyclohexene-1-carboxylic acid	482998: Displacement of [3H]niacin from GRP109A receptor	ic50	0.0050	uM
5-(3,5-difluorophenyl)-2-[[3-[1-(5-hydroxy-2-pyridinyl)pyrazol-3-yl]-2-methylpropanoyl]amino]cyclohexene-1-carboxylic acid	482998: Displacement of [3H]niacin from GRP109A receptor	ic50	0.0050	uM
(4S,5R)-2-[3-[3-(5-hydroxy-2-pyridinyl)-1,2,4-oxadiazol-5-yl]propanoylamino]-4-methyl-5-(2,3,5-trifluorophenyl)cyclohexene-1-carboxylic acid	484758: Agonist activity at human niacin receptor expressed in CHO-KI cells by [35S]GTPgammaS binding assay	ec50	0.0060	uM
2-[3-(6-fluoro-7-oxo-2H-benzo[g][1,2]benzoxazol-3-yl)propanoylamino]cyclohexene-1-carboxylic acid	353308: Displacement of [3H]niacin from human GPR109A expressed in CHO cells	ic50	0.0060	uM
5-butyl-2-[3-(6-hydroxynaphthalen-2-yl)propanoylamino]cyclohexene-1-carboxylic acid	484757: Displacement of [3H]niacin from human niacin receptor expressed in CHO-KI cells	ic50	0.0060	uM
4-(2,3-difluorophenyl)-2-[[3-[1-(5-hydroxy-2-pyridinyl)pyrazol-3-yl]-2-methylpropanoyl]amino]cyclohexene-1-carboxylic acid	482998: Displacement of [3H]niacin from GRP109A receptor	ic50	0.0060	uM
(4S,5R)-2-[3-[3-(5-fluoro-2-pyridinyl)-1,2,4-oxadiazol-5-yl]propanoylamino]-4-methyl-5-(2,3,5-trifluorophenyl)cyclohexene-1-carboxylic acid	484757: Displacement of [3H]niacin from human niacin receptor expressed in CHO-KI cells	ic50	0.0060	uM
5-(3-fluorophenyl)-2-[3-[3-(5-hydroxy-2-pyridinyl)-1,2,4-oxadiazol-5-yl]propanoylamino]cyclohexene-1-carboxylic acid	484757: Displacement of [3H]niacin from human niacin receptor expressed in CHO-KI cells	ic50	0.0070	uM
2-[3-[1-(5-hydroxy-2-pyridinyl)-5-methylpyrazol-4-yl]propanoylamino]cyclohexene-1-carboxylic acid	482998: Displacement of [3H]niacin from GRP109A receptor	ic50	0.0070	uM
5-[3-(1-chlorocyclopropyl)propyl]-1H-pyrano[2,3-d]pyrimidine-2,4,7-trione	663584: Agonist activity at human recombinant GPR109a expressed in CHO cells assessed as inhibition of forskolin-induced cAMP accumulation	ec50	0.0070	uM
5-(3-fluorophenyl)-2-[3-(6-hydroxynaphthalen-2-yl)propanoylamino]cyclohexene-1-carboxylic acid	484757: Displacement of [3H]niacin from human niacin receptor expressed in CHO-KI cells	ic50	0.0074	uM
(2R,3R,4S)-3-(cyclopropylmethyl)-8,9-diazatricyclo[4.3.0.02,4]nona-1(6),7-diene-7-carboxylic acid	672092: Agonist activity at human GPR109a expressed in CHO cells assessed as decrease in forskolin-stimulated cAMP production by HTRF assay	ec50	0.0074	uM
2-[3-(7-hydroxytriazolo[1,5-a]quinolin-3-yl)propanoylamino]benzoic acid	353308: Displacement of [3H]niacin from human GPR109A expressed in CHO cells	ic50	0.0080	uM
2-[3-[5-(2-chloro-4-hydroxyphenyl)thiophen-2-yl]propanoylamino]benzoic acid	1798331: Tritiated Niacin Binding Assay and [35S]-GTP-gammaS Binding Assay from Article 10.1021/jm700942d: “Discovery of biaryl anthranilides as full agonists for the high affinity niacin receptor.”	ic50	0.0080	uM
(4S,5R)-5-(3-fluorophenyl)-2-[3-[3-(5-hydroxy-2-pyridinyl)-1,2,4-oxadiazol-5-yl]propanoylamino]-4-methylcyclohexene-1-carboxylic acid	484757: Displacement of [3H]niacin from human niacin receptor expressed in CHO-KI cells	ic50	0.0080	uM
2-[3-(6-hydroxynaphthalen-2-yl)propanoylamino]cyclohexene-1-carboxylic acid	484757: Displacement of [3H]niacin from human niacin receptor expressed in CHO-KI cells	ic50	0.0080	uM
2-[3-(6-hydroxynaphthalen-2-yl)propanoylamino]-5-propylcyclohexene-1-carboxylic acid	484757: Displacement of [3H]niacin from human niacin receptor expressed in CHO-KI cells	ic50	0.0080	uM
5-(4-fluorophenyl)-2-[3-(6-hydroxynaphthalen-2-yl)propanoylamino]cyclohexene-1-carboxylic acid	484757: Displacement of [3H]niacin from human niacin receptor expressed in CHO-KI cells	ic50	0.0086	uM
niacin	301341: Agonist activity at human GPR109a expressed in human adipocytes assessed as decrease in intracellular cAMP level by HTRF assay	ec50	0.0087	uM
2-[3-[4-(5-hydroxy-2-pyridinyl)phenyl]propanoylamino]benzoic acid	1798331: Tritiated Niacin Binding Assay and [35S]-GTP-gammaS Binding Assay from Article 10.1021/jm700942d: “Discovery of biaryl anthranilides as full agonists for the high affinity niacin receptor.”	ic50	0.0090	uM
5-(6-fluoro-3-pyridinyl)-2-[3-[3-(5-hydroxy-2-pyridinyl)-1,2,4-oxadiazol-5-yl]propanoylamino]cyclohexene-1-carboxylic acid	484757: Displacement of [3H]niacin from human niacin receptor expressed in CHO-KI cells	ic50	0.0090	uM
2-[5-(2-chloro-4-hydroxyphenyl)pent-4-ynoylamino]cyclohexene-1-carboxylic acid	1487434: Agonist activity at recombinant human HCA2 receptor expressed in Flp-IN HEK cells assessed as reduction in forskolin-stimulated cAMP accumulation measured after 30 mins	ec50	0.0090	uM
2-[[3-[1-(5-hydroxy-2-pyridinyl)pyrazol-3-yl]-2-methylpropanoyl]amino]-4-propylcyclohexene-1-carboxylic acid	482998: Displacement of [3H]niacin from GRP109A receptor	ic50	0.0090	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Niacin	affects activity, increases phosphorylation, increases abundance, decreases reaction, increases activity (+3 more)	11
Cyclic AMP	increases abundance, increases activity, decreases abundance, affects binding, decreases reaction	3
Estradiol	affects cotreatment, decreases expression	3
sodium arsenite	decreases expression, increases expression	2
acifran	affects binding, increases activity, increases phosphorylation, increases reaction	2
Air Pollutants	decreases expression, increases abundance	2
Benzo(a)pyrene	decreases methylation, increases mutagenesis	2
Colforsin	increases abundance, increases activity, affects binding, decreases reaction	2
Nicotinic Acids	decreases reaction, increases activity, increases phosphorylation, affects binding, increases abundance (+1 more)	2
Pyrazoles	affects binding, increases activity	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
3-Hydroxybutyric Acid	affects binding, increases activity, decreases reaction, increases abundance	2
Particulate Matter	decreases expression, increases abundance	2
ortho-Aminobenzoates	affects binding, increases activity	2
aristolochic acid I	increases expression	1
GSK-J4	increases expression	1
bisphenol F	affects cotreatment, decreases expression	1
alpha phellandrene	increases expression	1
triphenyl phosphate	affects expression	1
cinnamic acid	affects binding	1
3-phenylpropionic acid	affects binding, increases activity	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
citraconic acid	increases activity, affects binding	1
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	decreases reaction, increases activity, increases phosphorylation	1
abrine	increases expression	1
gardiquimod	increases expression, decreases reaction	1
MK 6892	affects binding, increases activity	1
Leflunomide	increases expression	1
Arachidonic Acids	increases abundance, increases activity, increases phosphorylation, increases reaction	1

ChEMBL screening assays

135 unique, capped per target: 80 functional, 53 binding, 1 admet, 1 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1002173	Functional	Agonist activity against human GPR109a assessed as forskolin-induced cAMP accumulation	3-(1H-tetrazol-5-yl)-1,4,5,6-tetrahydro-cyclopentapyrazole (MK-0354): a partial agonist of the nicotinic acid receptor, G-protein coupled receptor 109a, with antilipolytic but no vasodilatory activity in mice. — *J Med Chem*
CHEMBL1002177	Binding	Displacement of [3H]nicotinic acid from human GPR109a receptor expressed in CHO cells	3-(1H-tetrazol-5-yl)-1,4,5,6-tetrahydro-cyclopentapyrazole (MK-0354): a partial agonist of the nicotinic acid receptor, G-protein coupled receptor 109a, with antilipolytic but no vasodilatory activity in mice. — *J Med Chem*
CHEMBL3788712	ADMET	Activation of GPR109A in human A431 cells assessed as suppression of forskolin-induced cAMP production after 30 mins	Synthesis and Characterization of Fatty Acid Conjugates of Niacin and Salicylic Acid. — *J Med Chem*

Cellosaurus cell lines

4 cell lines: 3 spontaneously immortalized cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_H469	CHO-K1/NIACR1/Galpha15	Spontaneously immortalized cell line	Female
CVCL_KV27	cAMP Hunter CHO-K1 GPR109A Gi	Spontaneously immortalized cell line	Female
CVCL_KX22	PathHunter CHO-K1 GPR109A beta-arrestin	Spontaneously immortalized cell line	Female
CVCL_ZL11	Tango GPR109A-bla U2OS	Cancer cell line	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for HCAR2 across ~30M SureChEMBL compounds — explore on Sugi Predict.