THRA

Summary

THRA (thyroid hormone receptor alpha, HGNC:11796) is a protein-coding gene on chromosome 17q21.1, encoding Thyroid hormone receptor alpha (P10827). Nuclear hormone receptor that can act as a repressor or activator of transcription.

The protein encoded by this gene is a nuclear hormone receptor for triiodothyronine. It is one of the several receptors for thyroid hormone, and has been shown to mediate the biological activities of thyroid hormone. Knockout studies in mice suggest that the different receptors, while having certain extent of redundancy, may mediate different functions of thyroid hormone. Alternatively spliced transcript variants encoding distinct isoforms have been reported.

Source: NCBI Gene 7067 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital nongoitrous hypothyroidism 6 (Definitive, GenCC)
• GWAS associations: 7
• Clinical variants (ClinVar): 96 total — 10 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 21
• Druggable target: yes — 12 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• Transcription factor: yes — 94 downstream targets (CollecTRI)
• MANE Select transcript: NM_199334

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11796
Approved symbol	THRA
Name	thyroid hormone receptor alpha
Location	17q21.1
Locus type	gene with protein product
Status	Approved
Aliases	EAR-7.1/EAR-7.2, THRA3, AR7, ERBA, NR1A1, TRalpha, TRalpha1, TRalpha2, c-ERBA-1, c-erbA, THRalpha, THRalpha1, THRalpha2
Ensembl gene	ENSG00000126351
Ensembl biotype	protein_coding
OMIM	190120
Entrez	7067

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 12 protein_coding, 1 retained_intron

ENST00000264637, ENST00000394121, ENST00000450525, ENST00000546243, ENST00000577288, ENST00000577486, ENST00000577637, ENST00000578218, ENST00000584985, ENST00000585047, ENST00000860601, ENST00000860602, ENST00000932773

RefSeq mRNA: 4 — MANE Select: NM_199334 NM_001190918, NM_001190919, NM_003250, NM_199334

CCDS: CCDS11360, CCDS42316, CCDS58546

Canonical transcript exons

ENST00000450525 — 9 exons

Exon	Start	End
ENSE00000863335	40086707	40086853
ENSE00001120400	40084610	40084815
ENSE00001182493	40076871	40076938
ENSE00001254896	40074192	40074541
ENSE00001302538	40083835	40083982
ENSE00001602007	40077508	40077608
ENSE00001736389	40089206	40093002
ENSE00001748430	40088242	40088500
ENSE00001876150	40062965	40063092

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 99.11.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.4157 / max 734.8969, expressed in 1788 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
160669	21.3118	1756
160667	3.8318	1384
160668	2.1012	917
160673	0.1216	42
160670	0.0492	27

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
nucleus accumbens	UBERON:0001882	99.11	gold quality
cortical plate	UBERON:0005343	98.97	gold quality
middle frontal gyrus	UBERON:0002702	98.66	gold quality
amygdala	UBERON:0001876	98.64	gold quality
caudate nucleus	UBERON:0001873	98.53	gold quality
putamen	UBERON:0001874	98.45	gold quality
right frontal lobe	UBERON:0002810	98.41	gold quality
cingulate cortex	UBERON:0003027	98.32	gold quality
anterior cingulate cortex	UBERON:0009835	98.30	gold quality
cerebellar hemisphere	UBERON:0002245	98.19	gold quality
cerebellar cortex	UBERON:0002129	98.16	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.09	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.85	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.84	gold quality
prefrontal cortex	UBERON:0000451	97.83	gold quality
cerebellum	UBERON:0002037	97.51	gold quality
sural nerve	UBERON:0015488	97.51	gold quality
spinal cord	UBERON:0002240	97.50	gold quality
hypothalamus	UBERON:0001898	97.39	gold quality
paraflocculus	UBERON:0005351	97.22	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.22	gold quality
telencephalon	UBERON:0001893	97.12	gold quality
ganglionic eminence	UBERON:0004023	97.09	gold quality
neocortex	UBERON:0001950	97.06	gold quality
frontal cortex	UBERON:0001870	97.04	gold quality
Brodmann (1909) area 10	UBERON:0013541	96.98	gold quality
Ammon’s horn	UBERON:0001954	96.97	gold quality
temporal lobe	UBERON:0001871	96.96	gold quality
cerebral cortex	UBERON:0000956	96.73	gold quality
forebrain	UBERON:0001890	96.71	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-5	yes	51.18
E-MTAB-7316	yes	13.60
E-ANND-3	yes	6.62

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

94 targets.

Target	Regulation
ABCA1	Unknown
ABCB1
ABCD2	Unknown
ADAM2
ANGPTL3
AP1
B3GNT9
BCO1
CA2	Repression
CAT
CD40
CD44
CDX1
CGA	Unknown
CHRNA3
CNOT2
CTNNB1	Unknown
CYP21A1P
CYP26A1
CYP27B1
CYP3A4
E2F1	Activation
EGFR
ELP1
ESR1	Repression
FN1	Activation
GCG
GFM1
GH1	Repression
GTF2B

JASPAR motifs

Motif	Name	Family
MA1969.1	THRA	Thyroid hormone receptor-related factors (NR1)
MA1969.2	THRA	Thyroid hormone receptor-related factors (NR1)

JASPAR matrix evidence (PMIDs): PMID:23332764

Upstream regulators (CollecTRI, top): AR, ESR1, ESRRA, ESRRB, MED1, MED25, NR0B2, RARA, THRA, TP53

miRNA regulators (miRDB)

26 targeting THRA, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-6738-3P	99.03	67.14	1326
HSA-MIR-1228-3P	99.00	66.53	857
HSA-MIR-5006-5P	98.79	66.92	1246
HSA-MIR-4755-3P	98.77	65.59	1915
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-323A-5P	98.59	65.13	651
HSA-MIR-3173-5P	97.35	65.82	1282
HSA-MIR-6799-3P	97.35	65.60	1302
HSA-MIR-597-5P	96.82	67.57	732
HSA-MIR-6735-3P	96.10	63.81	600
HSA-MIR-6514-5P	95.07	66.02	655

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• neurodevelopmental functions of thyroid hormone signaling. (PMID:11861164)
• affected receptor amino acid sequences. lost their trans-activation function and exhibited dominant negative activity. (PMID:11889175)
• Our results reveal specific alterations in the expression of TRbeta and TRalpha genes in a subset of breast cancer patients, suggesting that deregulation of thyroid hormone target genes may be involved in the generation of this neoplasia. (PMID:12082618)
• Less aggressive thyroid cancer was found to be linked to increased thyroid hormone receptor-alpha1 expression and an expanded THRA1 microsatellite. (PMID:12231529)
• allosteric changes resulting from binding of T3Ralpha to different response elements, i.e. pHREs versus nHREs, dictate whether a cofactor will function as a coactivator or a corepressor (PMID:12388540)
• the nTRE (negative thyroid hormone response element) is responsible for binding of thyroid hormone receptor alpha to the promoter in HeLa cells (PMID:12878587)
• Crucial in vivo functions of mutant TRalpha1s during mouse fetal development. Expression of dominant negative mutant TRalpha1 in extensive tissues from early embryonal stages might be lethal. (PMID:14614212)
• acquisition of altered nuclear export capabilities contributes to the oncogenic properties of v-ErbA (PMID:14729678)
• X-ray diffraction studies of isoform alpha1 of the human thyroid hormone receptor ligand-binding domain (PMID:15388935)
• Age-related hypo-activation of retinoic acid and triiodothyronine nuclear receptors in peripheral blood mononuclear cells. (PMID:15757863)
• T3 receptor mutants selectively impair beta2 isoform function in providing pituitary resistance to thyroid hormone syndrome (PMID:15802373)
• Thyroid hormone receptor (TR) D-domain has the potential to form functionally important extensions of the DNA-binding domain (DBD) and ligand-binding domain (LBD) or unfold to permit TRs to adapt to different DNA response elements. (PMID:16781732)
• Immunohistochemistry (demonstrated no overt difference between CDH, hypoplastic, and control lungs, either in the localization nor the timing of the first expression of glucocorticoid, retinoid, and thyroid hormone receptors (PMID:17065567)
• defects in adipogenesis could contribute to the phenotypic manifestation of reduced body weight in TRalpha1(PV/+) mice (PMID:17220280)
• the two systems, TRs and IGF1/IGF1R could be functionally associated. (PMID:17560756)
• These results suggest that inactivation of p44/42 MAPK enhances T(3)-induced GLUT5 gene expression in Caco-2 cells through increasing TRalpha-1 transactivity and binding activity to the GLUT5-TRE, probably due to de-phosphorylation of TRalpha-1. (PMID:17577579)
• We also found no methylation of the TRalpha gene in thyroid adenomas (PMID:17911173)
• both SMRT and N-CoR are limited in cells and knocking down either of them results in co-repressor-free TR and consequently de-repression of TR target genes (PMID:18052923)
• Furin overexpression in some types of hepatocellular carcinomas is TR dependent. (PMID:18467449)
• The DNA-binding domain of thyroid hormone receptor alpha plays a key role in direct DNA binding on positively but not on negatively triiodothyronine-regulated target genes. (PMID:18562675)
• TRalpha may follow a cooperative export pathway in which both calreticulin and CRM1 play a role in facilitating efficient translocation of TRalpha from the nucleus to cytoplasm (PMID:18641393)
• Two SNPs in the 3’ untranslated region of THRA were genotyped: a novel SNP (2390A/G) and 1895C/A (rs12939700). (PMID:18844476)
• The v-ErbA oncoprotein antagonizes TGF-beta signaling through its interaction with Smad4 and that v-ErbA association with Smad4 is essential for the dysregulation of TGF-beta signaling. (PMID:19144825)
• Genes for TR-alpha were differentially expressed in subcutaneous vs. omental adipose tissue. Findings suggest that TR alpha1 could contribute to SC adipose tissue expandability in obese subjects. (PMID:19360007)
• Triiodothyronine regulates AKR1B1 gene expression via a thyroxine receptor response element-dependant mechanism and associates liver cancer. (PMID:19422879)
• The relationship between the genetic variability of the THRA gene and Alzheimer disease risk remains uncertain but cannot be entirely excluded. (PMID:19427062)
• The SNP T594T (ESR1), but not the D6S440 (ESR1)and D17S189 (THRA)is associated with thyroid cancer risk. (PMID:19519176)
• analysis of isoform-specific transcriptional activity of overlapping target genes that respond to thyroid hormone receptors alpha1 and beta1 (PMID:19628582)
• Carboxi-terminal extension is required for acetylation, transactivation, transrepression, and antitransforming properties of TRalpha. (PMID:19819978)
• A bioassay to evaluate the thyroid disrupting potential of industrial chemical using human TRalpha or TRbeta in S. cerevisiae is described. (PMID:19853653)
• TR expression in human haematopoietic cells depends on thyroid function status, both hypo- and hyperthyroidism significantly influence clonogenicity and induce apoptosis in CD34(+)-enriched stem cells (PMID:19903799)
• The natural TH 3,5,3’-triodothyroacetic acid (Triac) exhibits a previously unrecognized mechanism of TRbeta selectivity. (PMID:19926848)
• A conserved lysine in the thyroid hormone receptor-alpha1 DNA-binding domain, mutated in hepatocellular carcinoma, is an allosteric sensor for transcription and contribute to neoplastic disease. (PMID:20053725)
• The presence of TRs in the penis provides the biological basis for the direct action of thyroid hormones on this organ. (PMID:20141582)
• Data suggest that CDK8 plays an important coactivator role in thyroid hormone receptor (TR)-dependent transcription by promoting Pol II recruitment and activation at TR target gene promoters. (PMID:20231357)
• We found TSHR, TRalpha1, TRalpha2 and TRbeta1 mRNA and proteins expressed in human endometrium (PMID:20691434)
• Patients with non-septic shock non-thyroidal illness syndrome show decreased expression of thyroid hormone receptors THRalpha1 and THRbeta in skeletal muscle. (PMID:20736347)
• Results highlight v-ErbA’s complex mode of action: the oncoprotein is highly mobile and trafficks between the nucleus, cytoplasm, and aggresome, carrying out distinct activities within each compartment. (PMID:21075170)
• Differential interaction of NCoR1 with TR isoforms accounted for the TR isoform-dependent regulation of adipogenesis and that aberrant interaction of NCoR1 with TR could underlie the pathogenesis of lipid disorders in hypothyroidism. (PMID:21389087)
• investigation of association/dissociation kinetics for recombinant TRalpha and ligand (125I-T3) (PMID:21508093)

Cross-species orthologs

189 orthologs

Organism	Symbol	Gene ID
danio_rerio	thraa	ENSDARG00000000151
danio_rerio	thrab	ENSDARG00000052654
mus_musculus	Thra	ENSMUSG00000058756
rattus_norvegicus	Thra	ENSRNOG00000009066
drosophila_melanogaster	EcR	FBGN0000546
drosophila_melanogaster	Hr96	FBGN0015240
caenorhabditis_elegans		WBGENE00001062
caenorhabditis_elegans	nhr-2	WBGENE00003601
caenorhabditis_elegans		WBGENE00003608
caenorhabditis_elegans		WBGENE00003611
caenorhabditis_elegans		WBGENE00003614
caenorhabditis_elegans		WBGENE00003615
caenorhabditis_elegans		WBGENE00003617
caenorhabditis_elegans		WBGENE00003618
caenorhabditis_elegans		WBGENE00003620
caenorhabditis_elegans	nhr-23	WBGENE00003622
caenorhabditis_elegans		WBGENE00003624
caenorhabditis_elegans		WBGENE00003632
caenorhabditis_elegans		WBGENE00003634
caenorhabditis_elegans		WBGENE00003638
caenorhabditis_elegans		WBGENE00003640
caenorhabditis_elegans		WBGENE00003641
caenorhabditis_elegans		WBGENE00003642
caenorhabditis_elegans		WBGENE00003643
caenorhabditis_elegans		WBGENE00003644
caenorhabditis_elegans		WBGENE00003645
caenorhabditis_elegans		WBGENE00003646
caenorhabditis_elegans		WBGENE00003648
caenorhabditis_elegans		WBGENE00003649
caenorhabditis_elegans		WBGENE00003651
caenorhabditis_elegans		WBGENE00003653
caenorhabditis_elegans		WBGENE00003655
caenorhabditis_elegans		WBGENE00003658
caenorhabditis_elegans		WBGENE00003660
caenorhabditis_elegans		WBGENE00003662
caenorhabditis_elegans	nhr-73	WBGENE00003663
caenorhabditis_elegans	nhr-77	WBGENE00003667
caenorhabditis_elegans		WBGENE00003669
caenorhabditis_elegans	nhr-81	WBGENE00003671
caenorhabditis_elegans	nhr-82	WBGENE00003672
caenorhabditis_elegans		WBGENE00003676
caenorhabditis_elegans		WBGENE00003677
caenorhabditis_elegans		WBGENE00003680
caenorhabditis_elegans		WBGENE00003682
caenorhabditis_elegans		WBGENE00003684
caenorhabditis_elegans		WBGENE00003685
caenorhabditis_elegans		WBGENE00003686
caenorhabditis_elegans		WBGENE00003688
caenorhabditis_elegans		WBGENE00003689
caenorhabditis_elegans		WBGENE00003692
caenorhabditis_elegans		WBGENE00003693
caenorhabditis_elegans		WBGENE00003694
caenorhabditis_elegans		WBGENE00003696
caenorhabditis_elegans		WBGENE00003698
caenorhabditis_elegans		WBGENE00003699
caenorhabditis_elegans		WBGENE00003700
caenorhabditis_elegans		WBGENE00003702
caenorhabditis_elegans		WBGENE00003704
caenorhabditis_elegans		WBGENE00003705
caenorhabditis_elegans		WBGENE00003707
caenorhabditis_elegans		WBGENE00003708
caenorhabditis_elegans		WBGENE00003712
caenorhabditis_elegans		WBGENE00003713
caenorhabditis_elegans		WBGENE00003714
caenorhabditis_elegans		WBGENE00003715
caenorhabditis_elegans		WBGENE00003716
caenorhabditis_elegans		WBGENE00003717
caenorhabditis_elegans		WBGENE00003718
caenorhabditis_elegans		WBGENE00003720
caenorhabditis_elegans		WBGENE00003721
caenorhabditis_elegans		WBGENE00003722
caenorhabditis_elegans		WBGENE00003723
caenorhabditis_elegans		WBGENE00003724
caenorhabditis_elegans		WBGENE00003725
caenorhabditis_elegans		WBGENE00003728
caenorhabditis_elegans		WBGENE00004786
caenorhabditis_elegans		WBGENE00006471
caenorhabditis_elegans	unc-55	WBGENE00006790
caenorhabditis_elegans		WBGENE00007367
caenorhabditis_elegans		WBGENE00008056
caenorhabditis_elegans	nhr-165	WBGENE00008158
caenorhabditis_elegans		WBGENE00008208
caenorhabditis_elegans	nhr-169	WBGENE00008289
caenorhabditis_elegans		WBGENE00008309
caenorhabditis_elegans	nhr-174	WBGENE00008474
caenorhabditis_elegans		WBGENE00008619
caenorhabditis_elegans		WBGENE00008630
caenorhabditis_elegans		WBGENE00008778
caenorhabditis_elegans		WBGENE00008830
caenorhabditis_elegans		WBGENE00008884
caenorhabditis_elegans		WBGENE00008901
caenorhabditis_elegans	nhr-265	WBGENE00009608
caenorhabditis_elegans		WBGENE00010017
caenorhabditis_elegans		WBGENE00010180
caenorhabditis_elegans		WBGENE00010186
caenorhabditis_elegans		WBGENE00010215
caenorhabditis_elegans		WBGENE00010410
caenorhabditis_elegans		WBGENE00010600
caenorhabditis_elegans		WBGENE00010601
caenorhabditis_elegans		WBGENE00010602
caenorhabditis_elegans		WBGENE00010603
caenorhabditis_elegans		WBGENE00010604
caenorhabditis_elegans		WBGENE00011002
caenorhabditis_elegans		WBGENE00011150
caenorhabditis_elegans		WBGENE00011396
caenorhabditis_elegans		WBGENE00011520
caenorhabditis_elegans		WBGENE00011565
caenorhabditis_elegans		WBGENE00011566
caenorhabditis_elegans		WBGENE00011568
caenorhabditis_elegans	nhr-217	WBGENE00011651
caenorhabditis_elegans		WBGENE00011750
caenorhabditis_elegans		WBGENE00012050
caenorhabditis_elegans		WBGENE00012056
caenorhabditis_elegans		WBGENE00012446
caenorhabditis_elegans		WBGENE00012449
caenorhabditis_elegans		WBGENE00012596
caenorhabditis_elegans		WBGENE00012703
caenorhabditis_elegans		WBGENE00013067
caenorhabditis_elegans		WBGENE00013483
caenorhabditis_elegans	nhr-276	WBGENE00013512
caenorhabditis_elegans		WBGENE00013584
caenorhabditis_elegans		WBGENE00013940
caenorhabditis_elegans		WBGENE00014068
caenorhabditis_elegans	nhr-245	WBGENE00014189
caenorhabditis_elegans		WBGENE00014193
caenorhabditis_elegans		WBGENE00015497
caenorhabditis_elegans		WBGENE00015758
caenorhabditis_elegans		WBGENE00015897
caenorhabditis_elegans		WBGENE00015900
caenorhabditis_elegans		WBGENE00015901
caenorhabditis_elegans		WBGENE00015902
caenorhabditis_elegans		WBGENE00016091
caenorhabditis_elegans		WBGENE00016233
caenorhabditis_elegans		WBGENE00016364
caenorhabditis_elegans		WBGENE00016365
caenorhabditis_elegans		WBGENE00016366
caenorhabditis_elegans		WBGENE00016367
caenorhabditis_elegans		WBGENE00016368
caenorhabditis_elegans		WBGENE00016517
caenorhabditis_elegans		WBGENE00016772
caenorhabditis_elegans		WBGENE00016926
caenorhabditis_elegans		WBGENE00016927
caenorhabditis_elegans		WBGENE00017503
caenorhabditis_elegans		WBGENE00017512
caenorhabditis_elegans		WBGENE00017961
caenorhabditis_elegans		WBGENE00018189
caenorhabditis_elegans		WBGENE00018265
caenorhabditis_elegans		WBGENE00018266
caenorhabditis_elegans		WBGENE00018404
caenorhabditis_elegans		WBGENE00018412
caenorhabditis_elegans		WBGENE00018415
caenorhabditis_elegans		WBGENE00018539
caenorhabditis_elegans		WBGENE00018541
caenorhabditis_elegans		WBGENE00018542
caenorhabditis_elegans		WBGENE00018544
caenorhabditis_elegans		WBGENE00018545
caenorhabditis_elegans		WBGENE00018622
caenorhabditis_elegans		WBGENE00019115
caenorhabditis_elegans		WBGENE00019116
caenorhabditis_elegans		WBGENE00019741
caenorhabditis_elegans		WBGENE00019742
caenorhabditis_elegans		WBGENE00019743
caenorhabditis_elegans		WBGENE00020015
caenorhabditis_elegans		WBGENE00020062
caenorhabditis_elegans		WBGENE00020152
caenorhabditis_elegans		WBGENE00020153
caenorhabditis_elegans		WBGENE00020385
caenorhabditis_elegans		WBGENE00020460
caenorhabditis_elegans		WBGENE00020555
caenorhabditis_elegans		WBGENE00020750
caenorhabditis_elegans		WBGENE00020849
caenorhabditis_elegans		WBGENE00020850
caenorhabditis_elegans		WBGENE00020851
caenorhabditis_elegans		WBGENE00020852
caenorhabditis_elegans		WBGENE00021163
caenorhabditis_elegans		WBGENE00021522
caenorhabditis_elegans		WBGENE00021610
caenorhabditis_elegans		WBGENE00021611
caenorhabditis_elegans		WBGENE00021617
caenorhabditis_elegans		WBGENE00022097
caenorhabditis_elegans		WBGENE00022637
caenorhabditis_elegans		WBGENE00022639
caenorhabditis_elegans		WBGENE00022640
caenorhabditis_elegans		WBGENE00022726
caenorhabditis_elegans		WBGENE00022756
caenorhabditis_elegans		WBGENE00022805
caenorhabditis_elegans		WBGENE00044353
caenorhabditis_elegans		WBGENE00044699
caenorhabditis_elegans		WBGENE00045515

Paralogs (18): NR1H4 (ENSG00000012504), NR1H3 (ENSG00000025434), RORA (ENSG00000069667), RARB (ENSG00000077092), VDR (ENSG00000111424), PPARD (ENSG00000112033), NR1D1 (ENSG00000126368), NR1H2 (ENSG00000131408), RARA (ENSG00000131759), PPARG (ENSG00000132170), NR1I3 (ENSG00000143257), RORC (ENSG00000143365), NR1I2 (ENSG00000144852), THRB (ENSG00000151090), RARG (ENSG00000172819), NR1D2 (ENSG00000174738), PPARA (ENSG00000186951), RORB (ENSG00000198963)

Protein

Protein identifiers

Thyroid hormone receptor alpha — P10827 (reviewed: P10827)

Alternative names: Nuclear receptor subfamily 1 group A member 1, V-erbA-related protein 7, c-erbA-1, c-erbA-alpha

All UniProt accessions (6): P10827, J3KTF3, J3QR26, J3QRA9, J3QRW5, Q6FH41

UniProt curated annotations — full annotation on UniProt →

Function. Nuclear hormone receptor that can act as a repressor or activator of transcription. High affinity receptor for thyroid hormones, including triiodothyronine and thyroxine. Does not bind thyroid hormone and functions as a weak dominant negative inhibitor of thyroid hormone action.

Subunit / interactions. Binds DNA as a dimer; homodimer and heterodimer with RXRB. Interacts with NCOA3 and NCOA6 coactivators, leading to a strong increase of transcription of target genes. Probably interacts with SFPQ. Interacts with C1D. Interacts with AKAP13. Interacts with TP53INP2. Interacts with PER2. Isoform alpha-2 and isoform alpha-1 interact with TACC1, but the interaction with alpha-1 is weaker. The interaction with isoform alpha-1, but not alpha-2, is decreased in the presence of thyroid hormone T3.

Subcellular location. Nucleus Cytoplasm. Nucleus.

Disease relevance. Hypothyroidism, congenital, non-goitrous, 6 (CHNG6) [MIM:614450] A disease characterized by growth retardation, developmental retardation, skeletal dysplasia, borderline low thyroxine levels and high triiodothyronine levels. There is differential sensitivity to thyroid hormone action, with retention of hormone responsiveness in the hypothalamic pituitary axis and liver but skeletal, gastrointestinal, and myocardial resistance. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Composed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal ligand-binding domain.

Miscellaneous. Does not bind thyroid hormone T3.

Similarity. Belongs to the nuclear hormone receptor family. NR1 subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
P10827-1	Alpha-2	yes
P10827-2	Alpha-1
P10827-3	Alpha-3
P10827-4	Alpha-4, Alpha3

RefSeq proteins (4): NP_001177847, NP_001177848, NP_003241, NP_955366* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000536	Nucl_hrmn_rcpt_lig-bd	Domain
IPR001628	Znf_hrmn_rcpt	Domain
IPR001723	Nuclear_hrmn_rcpt	Family
IPR001728	ThyrH_rcpt	Family
IPR013088	Znf_NHR/GATA	Homologous_superfamily
IPR035500	NHR-like_dom_sf	Homologous_superfamily
IPR050234	Nuclear_hormone_rcpt_NR1	Family

Pfam: PF00104, PF00105

UniProt features (53 total): helix 11, binding site 10, sequence variant 6, turn 6, strand 5, splice variant 3, sequence conflict 3, region of interest 3, zinc finger region 2, chain 1, domain 1, DNA-binding region 1, mutagenesis site 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
3ILZ	X-RAY DIFFRACTION	1.85
2H79	X-RAY DIFFRACTION	1.87
4LNW	X-RAY DIFFRACTION	1.9
3JZB	X-RAY DIFFRACTION	2.01
4LNX	X-RAY DIFFRACTION	2.05
2H77	X-RAY DIFFRACTION	2.33
1NAV	X-RAY DIFFRACTION	2.5
3HZF	X-RAY DIFFRACTION	2.5
8RQO	X-RAY DIFFRACTION	2.74
7QDT	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P10827-F1	74.23	0.48

Functional residue map

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

Ligand- & substrate-binding residues (10): 70; 73; 91; 97; 107; 110; 228; 277; 53; 56

Mutagenesis-validated functional residues (1):

Position	Phenotype
277	no effect on thyroid hormone binding.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-383280	Nuclear Receptor transcription pathway
R-HSA-4090294	SUMOylation of intracellular receptors
R-HSA-212436	Generic Transcription Pathway
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)

MSigDB gene sets: 387 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_EPITHELIUM_DEVELOPMENT, FREAC2_01, GOBP_LUNG_EPITHELIUM_DEVELOPMENT, GOBP_COGNITION, GOBP_BEHAVIOR, GOBP_MYELOID_CELL_HOMEOSTASIS, TGCGCANK_UNKNOWN, GOBP_CARTILAGE_DEVELOPMENT, GOBP_RESPONSE_TO_COLD, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GGGNRMNNYCAT_UNKNOWN, TGCACTT_MIR519C_MIR519B_MIR519A

GO Biological Process (30): negative regulation of transcription by RNA polymerase II (GO:0000122), cartilage condensation (GO:0001502), ossification (GO:0001503), thyroid hormone receptor signaling pathway (GO:0002154), positive regulation of thyroid hormone receptor signaling pathway (GO:0002157), regulation of transcription by RNA polymerase II (GO:0006357), transcription by RNA polymerase II (GO:0006366), learning or memory (GO:0007611), regulation of heart contraction (GO:0008016), female courtship behavior (GO:0008050), response to cold (GO:0009409), hormone-mediated signaling pathway (GO:0009755), negative regulation of RNA polymerase II transcription preinitiation complex assembly (GO:0017055), cell differentiation (GO:0030154), erythrocyte differentiation (GO:0030218), thyroid gland development (GO:0030878), regulation of myeloid cell apoptotic process (GO:0033032), mRNA transcription by RNA polymerase II (GO:0042789), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of female receptivity (GO:0045925), positive regulation of transcription by RNA polymerase II (GO:0045944), retinoic acid receptor signaling pathway (GO:0048384), regulation of lipid catabolic process (GO:0050994), type I pneumocyte differentiation (GO:0060509), positive regulation of cold-induced thermogenesis (GO:0120162), negative regulation of DNA-templated transcription initiation (GO:2000143), regulation of thyroid hormone receptor signaling pathway (GO:0002155), regulation of DNA-templated transcription (GO:0006355), animal organ morphogenesis (GO:0009887), intracellular receptor signaling pathway (GO:0030522)

GO Molecular Function (16): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription factor activity (GO:0003700), nuclear receptor activity (GO:0004879), zinc ion binding (GO:0008270), TBP-class protein binding (GO:0017025), protein domain specific binding (GO:0019904), chromatin DNA binding (GO:0031490), protein-containing complex binding (GO:0044877), thyroid hormone binding (GO:0070324), general transcription initiation factor binding (GO:0140296), DNA binding (GO:0003677), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565), metal ion binding (GO:0046872)

GO Cellular Component (6): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), RNA polymerase II transcription regulator complex (GO:0090575), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Generic Transcription Pathway	1
SUMO E3 ligases SUMOylate target proteins	1
RNA Polymerase II Transcription	1
Gene expression (Transcription)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
transcription by RNA polymerase II	3
regulation of DNA-templated transcription	3
regulation of transcription by RNA polymerase II	2
DNA-templated transcription	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
DNA binding	2
binding	2
negative regulation of DNA-templated transcription	1
skeletal system morphogenesis	1
cartilage development	1
cell aggregation	1
multicellular organismal process	1
hormone-mediated signaling pathway	1
nuclear receptor-mediated signaling pathway	1
thyroid hormone receptor signaling pathway	1
regulation of thyroid hormone receptor signaling pathway	1
positive regulation of intracellular signal transduction	1
behavior	1
cognition	1
heart contraction	1
regulation of blood circulation	1
courtship behavior	1
female mating behavior	1
response to stress	1
response to temperature stimulus	1
signal transduction	1
cellular response to hormone stimulus	1
negative regulation of protein-containing complex assembly	1
regulation of RNA polymerase II transcription preinitiation complex assembly	1
RNA polymerase II preinitiation complex assembly	1
negative regulation of transcription initiation by RNA polymerase II	1
cellular developmental process	1
myeloid cell differentiation	1
erythrocyte homeostasis	1
endocrine system development	1
gland development	1
myeloid cell apoptotic process	1
regulation of apoptotic process	1
mRNA transcription	1

Protein interactions and networks

STRING

1804 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
THRA	RXRA	P19793	867
THRA	TXNRD2	Q9NNW7	861
THRA	SLC16A2	P36021	670
THRA	CNOT6	Q9ULM6	655
THRA	NCOR1	O75376	642
THRA	TRH	P20396	638
THRA	DIO2	Q92813	633
THRA	NCOR2	Q9Y618	621
THRA	EGLN3	Q9H6Z9	616
THRA	TSHB	P01222	602
THRA	ESR1	P03372	598
THRA	NCOA3	Q9Y6Q9	592
THRA	FOS	P01100	581
THRA	CRYBA1	P05813	580
THRA	GALK1	P51570	576

IntAct

77 interactions, top by confidence:

A	B	Type	Score
THRA	CEP76	psi-mi:“MI:0915”(physical association)	0.670
MED1	THRA	psi-mi:“MI:0915”(physical association)	0.590
THRA	MED1	psi-mi:“MI:0915”(physical association)	0.590
L3MBTL3	THRA	psi-mi:“MI:0915”(physical association)	0.560
AMOTL2	THRA	psi-mi:“MI:0915”(physical association)	0.560
THRA	L3MBTL3	psi-mi:“MI:0915”(physical association)	0.560
THRA	AMOTL2	psi-mi:“MI:0915”(physical association)	0.560
THRA	SYAP1	psi-mi:“MI:0915”(physical association)	0.560
TACC1	THRA	psi-mi:“MI:0915”(physical association)	0.560
THRA	MEOX2	psi-mi:“MI:0915”(physical association)	0.560
CD160	THRA	psi-mi:“MI:0915”(physical association)	0.560
THRA	PRKAR1B	psi-mi:“MI:0915”(physical association)	0.560
THRA	Ncoa6	psi-mi:“MI:0915”(physical association)	0.510
THRA	AKT1	psi-mi:“MI:2364”(proximity)	0.470
THRA	AKT1	psi-mi:“MI:0915”(physical association)	0.470
AKAP13	THRA	psi-mi:“MI:0407”(direct interaction)	0.440
PKM	THRA	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
PIK3R1	THRA	psi-mi:“MI:0915”(physical association)	0.400
TXNRD1	THRA	psi-mi:“MI:0915”(physical association)	0.400
THRA	MTNR1B	psi-mi:“MI:0915”(physical association)	0.370
THRA		psi-mi:“MI:0915”(physical association)	0.370
	THRA	psi-mi:“MI:0915”(physical association)	0.370
IL31	THRA	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (171): AMOTL2 (Two-hybrid), L3MBTL3 (Two-hybrid), THRA (Affinity Capture-RNA), THRA (Affinity Capture-RNA), THRA (Affinity Capture-RNA), THRA (Reconstituted Complex), THRA (Biochemical Activity), THRA (Reconstituted Complex), CEP76 (Two-hybrid), THRA (Affinity Capture-Western), TRIM63 (Reconstituted Complex), THRA (Biochemical Activity), A2ML1 (Affinity Capture-MS), HAL (Affinity Capture-MS), CST6 (Affinity Capture-MS)

ESM2 similar proteins: A2T928, D3ZHS6, O42132, O75916, O88974, O93511, O97716, P03373, P10276, P10826, P10827, P11416, P13631, P18113, P18119, P18514, P18516, P18911, P22448, P22605, P28699, P37242, P49805, P51126, P57753, P63058, P63059, Q15047, Q1LUC3, Q28571, Q28C33, Q5FBR4, Q5RAP4, Q69ZT9, Q7ZTI3, Q80TJ7, Q90271, Q90966, Q91392, Q92831

Diamond homologs: A0JNE3, A2T928, A4IIG7, G5ECR9, G5EDJ0, O02151, O45666, O76202, O97716, P10276, P10588, P10826, P10827, P10828, P11416, P12813, P13056, P13631, P16376, P18117, P18514, P18515, P18516, P18911, P20153, P22448, P22449, P22605, P22736, P22829, P28699, P31396, P33242, P33244, P41828, P41830, P43354, P45447, P49116, P49117

SIGNOR signaling

18 interactions.

A	Effect	B	Mechanism
NR0B2	“down-regulates quantity by repression”	THRA	“transcriptional regulation”
RARA	up-regulates	THRA	binding
RARB	up-regulates	THRA	binding
RARG	up-regulates	THRA	binding
THRA	up-regulates	RARA	binding
THRA	up-regulates	RARB	binding
THRA	up-regulates	RARG	binding
D-thyroxine	“up-regulates activity”	THRA	“chemical activation”
3,3’,5’-triiodothyronine	“up-regulates activity”	THRA	binding
THRA	“down-regulates activity”	GATA2	binding
THRA	“up-regulates quantity by expression”	OXT	“transcriptional regulation”
THRA	up-regulates	RAR	binding
RAR	up-regulates	THRA	binding
TRIP11	up-regulates	THRA	binding
RXRA	up-regulates	THRA	binding
RXRB	up-regulates	THRA	binding
L-thyroxine	“up-regulates activity”	THRA	“chemical activation”
3,3’,5’-triiodothyronine	“up-regulates activity”	THRA	“chemical activation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 35 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
cellular response to epidermal growth factor stimulus	5	46.8×	4e-05
phosphatidylinositol 3-kinase/protein kinase B signal transduction	5	31.0×	2e-04
heart development	5	11.6×	4e-03
angiogenesis	5	9.2×	8e-03
protein ubiquitination	6	7.3×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	7
Uncertain significance	39
Likely benign	13
Benign	6

Top pathogenic / likely-pathogenic (17)

Variant ID	HGVS	Classification
1186100	NM_199334.5(THRA):c.871G>A (p.Gly291Ser)	Pathogenic
1216462	NM_199334.5(THRA):c.1150C>T (p.Arg384Cys)	Pathogenic
192271	NM_199334.5(THRA):c.1176C>A (p.Cys392Ter)	Pathogenic
192272	NM_199334.5(THRA):c.1207G>A (p.Glu403Lys)	Pathogenic
192273	NM_199334.5(THRA):c.1193C>G (p.Pro398Arg)	Pathogenic
29913	NM_199334.5(THRA):c.134G>T (p.Ser45Ile)	Pathogenic
29914	NM_199334.5(THRA):c.1110G>C (p.Lys370Asn)	Pathogenic
3340286	NM_199334.5(THRA):c.1151G>A (p.Arg384His)	Pathogenic
4184168	NM_199334.5(THRA):c.1196dup (p.Leu400fs)	Pathogenic
520565	NM_199334.5(THRA):c.1137del (p.Cys380fs)	Pathogenic
1064765	NM_199334.5(THRA):c.1132_1141del (p.Gly378fs)	Likely pathogenic
1679212	NM_199334.5(THRA):c.818C>A (p.Thr273Asn)	Likely pathogenic
3024267	NM_199334.5(THRA):c.896T>C (p.Ile299Thr)	Likely pathogenic
3254965	NM_199334.5(THRA):c.1141C>T (p.His381Tyr)	Likely pathogenic
3337670	NM_199334.5(THRA):c.872G>A (p.Gly291Asp)	Likely pathogenic
847657	NM_199334.5(THRA):c.641C>G (p.Ala214Gly)	Likely pathogenic
992628	NM_199334.5(THRA):c.518A>G (p.Glu173Gly)	Likely pathogenic

SpliceAI

1428 predictions. Top by Δscore:

Variant	Effect	Δscore
17:40063090:GAGGT:G	donor_loss	1.0000
17:40083831:CCA:C	acceptor_loss	1.0000
17:40083832:CA:C	acceptor_loss	1.0000
17:40083833:A:AC	acceptor_loss	1.0000
17:40083833:A:AG	acceptor_gain	1.0000
17:40083833:AG:A	acceptor_gain	1.0000
17:40083833:AGG:A	acceptor_gain	1.0000
17:40083834:G:A	acceptor_loss	1.0000
17:40083834:G:GG	acceptor_gain	1.0000
17:40083834:GG:G	acceptor_gain	1.0000
17:40083834:GGG:G	acceptor_gain	1.0000
17:40083834:GGGC:G	acceptor_gain	1.0000
17:40083951:G:GT	donor_gain	1.0000
17:40083978:GGACT:G	donor_gain	1.0000
17:40083979:G:GT	donor_gain	1.0000
17:40083979:GACT:G	donor_gain	1.0000
17:40083980:A:T	donor_gain	1.0000
17:40083980:ACT:A	donor_gain	1.0000
17:40083980:ACTG:A	donor_loss	1.0000
17:40083981:CT:C	donor_gain	1.0000
17:40083981:CTGT:C	donor_loss	1.0000
17:40083982:TGTAA:T	donor_loss	1.0000
17:40083983:G:GG	donor_gain	1.0000
17:40083983:GTAA:G	donor_loss	1.0000
17:40084606:ACAGT:A	acceptor_gain	1.0000
17:40084607:C:G	acceptor_gain	1.0000
17:40084607:CAG:C	acceptor_loss	1.0000
17:40084608:A:AG	acceptor_gain	1.0000
17:40084608:AGT:A	acceptor_gain	1.0000
17:40084608:AGTG:A	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000020740 (17:40081779 C>T), RS1000047973 (17:40075074 G>A), RS1000218862 (17:40087211 A>G), RS1000279063 (17:40063586 G>A), RS1000329559 (17:40063604 TTCCCCCGCC>T), RS1000380738 (17:40069512 C>T), RS1000494981 (17:40065542 C>G), RS1000565941 (17:40063830 C>T), RS1000655292 (17:40071345 T>C), RS1000737935 (17:40093882 T>C), RS1000886847 (17:40076051 C>T), RS1001070280 (17:40064876 C>G,T), RS1001110500 (17:40087142 C>T), RS1001258812 (17:40082357 G>A), RS1001339408 (17:40093819 C>A,G,T)

Disease associations

OMIM: gene MIM:190120 | disease phenotypes: MIM:614450

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital nongoitrous hypothyroidism 6	Definitive	Autosomal dominant

Mondo (2): neurodevelopmental disorder (MONDO:0700092), congenital nongoitrous hypothyroidism 6 (MONDO:0013757)

Orphanet (1): OBSOLETE: Peripheral resistance to thyroid hormones (Orphanet:97927)

HPO phenotypes

21 total (21 of 21 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000158	Macroglossia
HP:0000316	Hypertelorism
HP:0000684	Delayed eruption of teeth
HP:0000851	Congenital hypothyroidism
HP:0000958	Dry skin
HP:0001374	Congenital hip dislocation
HP:0001510	Growth delay
HP:0001539	Omphalocele
HP:0001609	Hoarse voice
HP:0001903	Anemia
HP:0002019	Constipation
HP:0002136	Broad-based gait
HP:0002329	Drowsiness
HP:0002645	Wormian bones
HP:0002750	Delayed skeletal maturation
HP:0002930	Impaired sensitivity to thyroid hormone
HP:0004324	Increased body weight
HP:0004482	Relative macrocephaly
HP:0012559	Increased T3/T4 ratio
HP:0031418	Increased body mass index

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001137_10	White blood cell count	9.000000e-35
GCST001137_8	White blood cell count	2.000000e-31
GCST007235_9	Pancreatic ductal adenocarcinoma	7.000000e-06
GCST007692_78	Chronic obstructive pulmonary disease	8.000000e-09
GCST008103_61	Bipolar disorder	6.000000e-07
GCST008916_21	Asthma	2.000000e-62
GCST008916_85	Asthma	2.000000e-12

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004833	neutrophil count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1860 (SINGLE PROTEIN), CHEMBL2111462 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

12 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 189,460 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1544	LIOTHYRONINE	4	23,700
CHEMBL1624	LEVOTHYROXINE	4	81,643
CHEMBL2338329	ROXADUSTAT	4	1,063
CHEMBL3261331	RESMETIROM	4	1,315
CHEMBL633	AMIODARONE	4	29,704
CHEMBL2035874	EPROTIROME	3	486
CHEMBL41632	TIRATRICOL	3	46,632
CHEMBL107400	SOBETIROME	2	1,113
CHEMBL159682	AXITIROME	2	1,200
CHEMBL291053	THYROPROPIC ACID	2	729
CHEMBL471897	MB07811	2	18
CHEMBL557	DETROTHYRONINE	2	1,857

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

PharmGKB clinical annotations

3 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs11819745	Toxicity	3	aspirin	Aspirin-induced asthma;Asthma
rs2071427	Efficacy	3	lithium	Bipolar Disorder
rs2314339	Efficacy	3	lithium	Bipolar Disorder

PharmGKB variants

5 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs11819745	THRA	3	3.00	1	aspirin
rs2071427	NR1D1, THRA	3	0.25	1	lithium
rs2269457	NR1D1, THRA		0.00	0
rs2314339	NR1D1, THRA	3	2.50	1	lithium
rs4794826	NR1D1, THRA		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: nhr — 1A. Thyroid hormone receptors

Most potent curated ligand interactions (6 total), top 6:

Ligand	Action	Affinity	Parameter
triiodothyronine	Agonist	10.0	pKd
sobetirome	Agonist	9.36	pKd
NH-3	Antagonist	7.62	pKd
KB-141	Agonist	7.6	pIC50
VK2809	Agonist	7.45	pKi
resmetirom	Agonist	5.43	pEC50

Binding affinities (BindingDB)

188 measured of 229 human assays (231 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
3-{3,5-dibromo-4-[4-hydroxy-3-(propan-2-yl)phenoxy]phenyl}propanoic acid	IC50	0.1 nM
(2R)-2-amino-3-{4-[4-hydroxy-3-(propan-2-yl)phenoxy]-3,5-diiodophenyl}propanoic acid	IC50	0.14 nM
3-{3,5-dichloro-4-[4-hydroxy-3-(propan-2-yl)phenoxy]phenyl}propanoic acid	EC50	0.3 nM
dibromo phenylacetic acid, 11a	EC50	0.38 nM
2-[3,5-dibromo-4-(cyclohexylmethoxy)phenyl]acetic acid	EC50	0.42 nM
3,5-dimethyl-4-(4’-hydroxy-3’-isopropylbenzyl)phenoxyacetic acid	KD	0.44 nM
JMC496635 Compound 9	EC50	0.53 nM
3-[3,5-dibromo-4-(hexyloxy)phenyl]propanoic acid	EC50	0.6 nM
2-[3,5-dibromo-4-(hexyloxy)phenyl]acetic acid	EC50	0.7 nM
2-[3,5-dibromo-4-(2-ethylbutoxy)phenyl]acetic acid	EC50	0.82 nM
(2S)-2-(1-{3,5-dibromo-4-[4-hydroxy-3-(propan-2-yl)phenoxy]phenyl}acetamido)-3-methylbutanoic acid	EC50	1.4 nM
(2R)-2-(1-{3,5-dibromo-4-[4-hydroxy-3-(propan-2-yl)phenoxy]phenyl}acetamido)-2-phenylacetic acid	EC50	1.5 nM
2-{3,5-dichloro-4-[4-hydroxy-3-(propan-2-yl)phenoxy]phenyl}acetic acid	EC50	1.7 nM
(2R)-2-(1-{3,5-dibromo-4-[4-hydroxy-3-(propan-2-yl)phenoxy]phenyl}acetamido)-3-methylbutanoic acid	EC50	2.3 nM
(2S)-2-(1-{3,5-dibromo-4-[4-hydroxy-3-(propan-2-yl)phenoxy]phenyl}acetamido)propanoic acid	EC50	7.2 nM
(2S)-2-(1-{3,5-dibromo-4-[4-hydroxy-3-(propan-2-yl)phenoxy]phenyl}acetamido)-2-phenylacetic acid	IC50	7.5 nM
3,5-dibromo-4-[4-hydroxy-3-(propan-2-yl)phenoxy]benzoic acid	IC50	9.7 nM
2-Amino-3-[4-(4-hydroxy-3-isopropyl-phenoxy)-3,5-dimethyl-phenyl]-propionic acid	KD	9.7 nM
CO23	EC50	11 nM
2-{3,5-dichloro-4-[3-(3-ethylphenyl)-4-hydroxyphenoxy]phenyl}acetic acid	IC50	13 nM
(2R)-2-(1-{3,5-dibromo-4-[4-hydroxy-3-(propan-2-yl)phenoxy]phenyl}acetamido)propanoic acid	EC50	15 nM
2-(3,5-dibromo-4-{4-hydroxy-3-[(2-phenylethyl)carbamoyl]phenoxy}phenyl)acetic acid	IC50	15 nM
(2S)-2-(1-{3,5-dibromo-4-[3-fluoro-4-hydroxy-5-(propan-2-yl)phenoxy]phenyl}acetamido)-3-methylbutanoic acid	EC50	17 nM
2-(3,5-dichloro-4-{4-hydroxy-3-[2-(trifluoromethyl)phenyl]phenoxy}phenyl)acetic acid	IC50	18 nM
2-(3,5-dibromo-4-{3-[(2,2-diphenylethyl)carbamoyl]-4-hydroxyphenoxy}phenyl)acetic acid	IC50	18 nM
3-(3,5-dibromo-4-{[3-(ethylamino)phenyl]methoxy}phenyl)propanoic acid	EC50	23 nM
2-(1-{3,5-dibromo-4-[4-hydroxy-3-(propan-2-yl)phenoxy]phenyl}acetamido)acetic acid	IC50	26 nM
2-(3,5-dichloro-4-{3-[3-(difluoromethoxy)phenyl]-4-hydroxyphenoxy}phenyl)acetic acid	IC50	30 nM
3-{3,5-dibromo-4-[4-hydroxy-3-(propan-2-yl)-5-[(E)-2-(pyridin-4-yl)ethenyl]phenoxy]phenyl}propanoic acid	EC50	32 nM
2-(3,5-dichloro-4-{4-hydroxy-3-[3-(trifluoromethyl)phenyl]phenoxy}phenyl)acetic acid	IC50	40 nM
2-(3,5-dibromo-4-{4-hydroxy-3-[3-(trifluoromethyl)phenoxy]phenoxy}phenyl)acetic acid	IC50	50 nM
(2S)-2-(1-{3,5-dibromo-4-[3-chloro-4-hydroxy-5-(propan-2-yl)phenoxy]phenyl}acetamido)-3-methylbutanoic acid	EC50	65 nM
(2S)-2-(1-{3,5-dibromo-4-[4-hydroxy-3-(propan-2-yl)phenoxy]phenyl}acetamido)-4-hydroxybutanoic acid	EC50	66 nM
2-{4-[3-(benzylcarbamoyl)-4-hydroxyphenoxy]-3,5-dibromophenyl}acetic acid	IC50	84 nM
JMC496635 Compound 5	IC50	93 nM
2-[3,5-dibromo-4-(4-hydroxy-3-{[2-(3-methoxyphenyl)ethyl]carbamoyl}phenoxy)phenyl]acetic acid	IC50	93 nM
2-[3,5-dibromo-4-(4-hydroxy-3-{[2-(2-methoxyphenyl)ethyl]carbamoyl}phenoxy)phenyl]acetic acid	IC50	96 nM
3-{3,5-dibromo-4-[(3-bromophenyl)methoxy]phenyl}propanoic acid	IC50	99 nM
2-(3,5-dichloro-4-{4-hydroxy-3-[3-(trifluoromethoxy)phenyl]phenoxy}phenyl)acetic acid	IC50	100 nM
2-[3,5-dibromo-4-(4-hydroxy-3-phenoxyphenoxy)phenyl]acetic acid	IC50	123 nM
2-(3,5-dichloro-4-{4-hydroxy-3-[3-(propan-2-yl)phenyl]phenoxy}phenyl)acetic acid	IC50	124 nM
2-(3,5-dichloro-4-{4-hydroxy-3-[(2-phenylethyl)carbamoyl]phenoxy}phenyl)acetic acid	IC50	127 nM
3,5-dichloro-4-[4-hydroxy-3-(propan-2-yl)phenoxy]benzoic acid	IC50	130 nM
2-[3-chloro-4-[(3-propan-2-yl-1H-indol-5-yl)oxy]-5-(trifluoromethyl)phenyl]-3,5-dioxo-1,2,4-triazine-6-carbonitrile	EC50	140 nM	US-12391677: Thyroid hormone receptor agonists
2-{3,5-dichloro-4-[4-hydroxy-3-(pyridin-4-yl)phenoxy]phenyl}acetic acid	IC50	145 nM
2-[3,5-dichloro-4-(4-hydroxy-3-phenylphenoxy)phenyl]acetic acid	IC50	152 nM
(2S)-2-(1-{3,5-dibromo-4-[4-hydroxy-3-methyl-5-(propan-2-yl)phenoxy]phenyl}acetamido)-3-methylbutanoic acid	EC50	170 nM
JMC496635 Compound 4	IC50	200 nM
2-(3,5-dibromo-4-{4-hydroxy-3-[(3-phenylpropyl)carbamoyl]phenoxy}phenyl)acetic acid	IC50	203 nM
2-[3,5-dibromo-4-(4-hydroxy-3-{[2-(4-methoxyphenyl)ethyl]carbamoyl}phenoxy)phenyl]acetic acid	IC50	228 nM

ChEMBL bioactivities

551 potent at pChembl≥5 of 608 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.39	IC50	0.041	nM	THYROPROPIC ACID
10.39	IC50	0.04074	nM	THYROPROPIC ACID
10.24	Kd	0.058	nM	LIOTHYRONINE
10.22	Kd	0.06	nM	LIOTHYRONINE
10.22	EC50	0.06	nM	CHEMBL392666
10.10	EC50	0.08	nM	CHEMBL248111
10.00	IC50	0.1	nM	CHEMBL289343
10.00	Kd	0.1	nM	LIOTHYRONINE
9.85	IC50	0.14	nM	TIRATRICOL
9.85	IC50	0.14	nM	CHEMBL41314
9.85	IC50	0.1413	nM	CHEMBL41314
9.85	IC50	0.1413	nM	TIRATRICOL
9.77	Kd	0.17	nM	LIOTHYRONINE
9.70	EC50	0.2	nM	CHEMBL182339
9.66	Ki	0.22	nM	LIOTHYRONINE
9.62	IC50	0.24	nM	DETROTHYRONINE
9.62	IC50	0.24	nM	LIOTHYRONINE
9.62	IC50	0.2399	nM	DETROTHYRONINE
9.52	EC50	0.3	nM	CHEMBL418432
9.52	EC50	0.3	nM	CHEMBL248515
9.48	Ki	0.33	nM	LIOTHYRONINE
9.46	Ki	0.35	nM	CHEMBL3397337
9.42	EC50	0.38	nM	CHEMBL39174
9.42	Ki	0.38	nM	CHEMBL3397339
9.39	EC50	0.41	nM	LIOTHYRONINE
9.30	EC50	0.5	nM	CHEMBL361162
9.30	EC50	0.5	nM	LIOTHYRONINE
9.30	EC50	0.5	nM	CHEMBL594025
9.29	Ki	0.51	nM	CHEMBL3397341
9.29	Ki	0.51	nM	CHEMBL46882
9.18	Kd	0.66	nM	SOBETIROME
9.16	Kd	0.69	nM	CHEMBL322361
9.15	EC50	0.7	nM	LIOTHYRONINE
9.15	Ki	0.7	nM	CHEMBL608990
9.12	IC50	0.76	nM	CHEMBL418432
9.12	IC50	0.7586	nM	CHEMBL418432
9.00	EC50	1.01	nM	LIOTHYRONINE
8.96	Ki	1.09	nM	CHEMBL3397336
8.96	Ki	1.09	nM	SOBETIROME
8.92	EC50	1.2	nM	CHEMBL360137
8.92	Kd	1.2	nM	CHEMBL263630
8.89	EC50	1.3	nM	DETROTHYRONINE
8.85	IC50	1.4	nM	CHEMBL39174
8.85	IC50	1.4	nM	CHEMBL203777
8.85	IC50	1.413	nM	CHEMBL203777
8.81	IC50	1.549	nM	CHEMBL39174
8.74	Kd	1.8	nM	SOBETIROME
8.73	Ki	1.84	nM	CHEMBL512383
8.70	EC50	2	nM	LIOTHYRONINE
8.70	Kd	2.02	nM	CHEMBL110335

PubChem BioAssay actives

633 with measured affinity, of 1258 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
3-[4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl]propanoic acid	1797782: TRalpha-Binding Assay. from Article 10.1021/jm021080f: “Thyroid receptor ligands. 1. Agonist ligands selective for the thyroid receptor beta1.”	ic50	<0.0001	uM
5-[[4-(4-hydroxy-3-propan-2-ylphenoxy)-3,5-dimethylphenyl]methyl]-1,3-thiazolidine-2,4-dione	307878: Agonist activity at THR in HepG2 cells by whole cell assay	ec50	0.0001	uM
3-[3,5-dibromo-4-(4-hydroxy-3-propan-2-ylphenoxy)phenyl]propanoic acid	1797782: TRalpha-Binding Assay. from Article 10.1021/jm021080f: “Thyroid receptor ligands. 1. Agonist ligands selective for the thyroid receptor beta1.”	ic50	0.0001	uM
(2R)-2-amino-3-[4-(4-hydroxy-3-propan-2-ylphenoxy)-3,5-diiodophenyl]propanoic acid	1797782: TRalpha-Binding Assay. from Article 10.1021/jm021080f: “Thyroid receptor ligands. 1. Agonist ligands selective for the thyroid receptor beta1.”	ic50	0.0001	uM
6-[[3-(4-hydroxy-3-propan-2-ylphenoxy)-2,4-dimethylphenyl]methyl]-1,3-thiazinane-2,4-dione	307878: Agonist activity at THR in HepG2 cells by whole cell assay	ec50	0.0001	uM
2-[4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl]acetic acid	1797782: TRalpha-Binding Assay. from Article 10.1021/jm021080f: “Thyroid receptor ligands. 1. Agonist ligands selective for the thyroid receptor beta1.”	ic50	0.0001	uM
Liothyronine	1799413: Competition Binding Assay from Article 10.1021/cb600311v: “Design and characterization of a thyroid hormone receptor alpha (TRalpha)-specific agonist.”	kd	0.0001	uM
(2S)-2-amino-3-[4-(4-hydroxy-3-iodophenoxy)-3-iodo-5-methylphenyl]propanoic acid	240275: Agonist activity towards thyroid hormone receptor expressed in human HepG2 cells	ec50	0.0002	uM
(2R)-2-amino-3-[4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl]propanoic acid	213163: Concentration required to inhibit 50% of I-T3 binding to hTR1 (Thyroid hormone receptor alpha) was determined	ic50	0.0002	uM
3-[3,5-dichloro-4-(4-hydroxy-3-propan-2-ylphenoxy)phenyl]propanoic acid	213162: Effect on CHO-K1 cells stably transfected with Thyroid hormone receptor alpha (TRalpha1) and an alkaline phosphate reporter gene downstream thyroid response element TRAF-alpha1 was determined	ec50	0.0003	uM
2-[7-chloro-1-[(4-hydroxy-3-propan-2-ylphenyl)methyl]indol-5-yl]oxyacetic acid	1192348: Displacement of [125I]-L-3,5,3’-triiodothyronine from human TRalpha expressed in human Hela cell lysate measured after overnight incubation by competition binding assays	ki	0.0003	uM
2-[6-(4-hydroxy-3-propan-2-ylphenoxy)-5,7-dimethyl-1-benzofuran-3-yl]acetic acid	307878: Agonist activity at THR in HepG2 cells by whole cell assay	ec50	0.0003	uM
2-[7-chloro-1-[(4-hydroxy-3-propan-2-ylphenyl)methyl]-2-methylindol-5-yl]oxyacetic acid	1192348: Displacement of [125I]-L-3,5,3’-triiodothyronine from human TRalpha expressed in human Hela cell lysate measured after overnight incubation by competition binding assays	ki	0.0004	uM
2-[4-[(4-hydroxy-3-propan-2-ylphenyl)methyl]-3,5-dimethylphenoxy]acetic acid	1799448: TR Receptor Ligand Binding Assay from Article 10.1016/s1074-5521(98)90168-5: “A high-affinity subtype-selective agonist ligand for the thyroid hormone receptor.”	kd	0.0004	uM
2-[3,5-dibromo-4-(4-hydroxy-3-propan-2-ylphenoxy)phenyl]acetic acid	213162: Effect on CHO-K1 cells stably transfected with Thyroid hormone receptor alpha (TRalpha1) and an alkaline phosphate reporter gene downstream thyroid response element TRAF-alpha1 was determined	ec50	0.0004	uM
2-[4-[3-[(4-fluorophenyl)methyl]-4-hydroxyphenoxy]-3,5-dimethylphenyl]-1,2,4-triazine-3,5-dione	454516: Binding affinity to thyroid hormone receptor in human HepG2 cells	ec50	0.0005	uM
2-[7-chloro-1-[(4-hydroxy-3-propan-2-ylphenyl)methyl]-3-methylindol-5-yl]oxyacetic acid	1192348: Displacement of [125I]-L-3,5,3’-triiodothyronine from human TRalpha expressed in human Hela cell lysate measured after overnight incubation by competition binding assays	ki	0.0005	uM
2-[4-[(3-propan-2-yl-1H-indol-5-yl)oxy]-3,5-bis(trifluoromethyl)phenyl]acetic acid	240275: Agonist activity towards thyroid hormone receptor expressed in human HepG2 cells	ec50	0.0005	uM
2-[4-(4-hydroxy-3-propan-2-ylphenoxy)-3,5-dimethylanilino]-2-oxoacetic acid	345695: Displacement of [125I]3,5,3’-triiodo-L-thyronine from His-tagged human recombinant TRalpha1 by scintillation proximity assay	ki	0.0005	uM
3-[4-[(4-hydroxy-3-propan-2-ylphenyl)methyl]-3,5-dimethylphenyl]propanoic acid	213173: Binding affinity of compound was determined against Thyroid hormone receptor alpha1	kd	0.0007	uM
2-[4-[(7-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy]-3,5-dimethylanilino]-2-oxoacetic acid	454514: Binding affinity to thyroid receptor alpha	ki	0.0007	uM
2-[1-[(4-hydroxy-3-propan-2-ylphenyl)methyl]-7-methylindol-5-yl]oxyacetic acid	1192348: Displacement of [125I]-L-3,5,3’-triiodothyronine from human TRalpha expressed in human Hela cell lysate measured after overnight incubation by competition binding assays	ki	0.0011	uM
ethyl 2-[3,5-dibromo-4-[(3-propan-2-yl-1H-indol-5-yl)oxy]anilino]-2-oxoacetate	240275: Agonist activity towards thyroid hormone receptor expressed in human HepG2 cells	ec50	0.0012	uM
5-[[4-(4-hydroxy-3-propan-2-ylphenoxy)-3,5-diiodophenyl]methyl]imidazolidine-2,4-dione	323174: Displacement of [125I]T3 from human TRalpha receptor	kd	0.0012	uM
4-hydroxy-5-[[4-(4-hydroxy-3-propan-2-ylphenoxy)-3,5-diiodophenyl]methyl]-1,3-dihydroimidazol-2-one	1799413: Competition Binding Assay from Article 10.1021/cb600311v: “Design and characterization of a thyroid hormone receptor alpha (TRalpha)-specific agonist.”	kd	0.0012	uM
4,6-dichloro-5-(4-hydroxy-3-propan-2-ylphenoxy)-1H-indole-2-carboxylic acid	261712: Inhibition of human TR-alpha-1 by radioligand binding assay	ic50	0.0014	uM
[4-(4-hydroxy-3-propan-2-ylphenoxy)-3,5-diiodophenyl]methylphosphonic acid	345695: Displacement of [125I]3,5,3’-triiodo-L-thyronine from His-tagged human recombinant TRalpha1 by scintillation proximity assay	ki	0.0018	uM
(2S)-2-amino-3-[4-[(4-hydroxy-3-propan-2-ylphenyl)methyl]-3,5-dimethylphenyl]propanoic acid	213173: Binding affinity of compound was determined against Thyroid hormone receptor alpha1	kd	0.0020	uM
3-[3-chloro-4-[3-(cyclobutylmethylsulfonyl)-4-hydroxyphenoxy]-5-methylanilino]-3-oxopropanoic acid	454514: Binding affinity to thyroid receptor alpha	ki	0.0021	uM
2-[1-[(4-hydroxy-3-propan-2-ylphenyl)methyl]-2,7-dimethylindol-5-yl]oxyacetic acid	1192348: Displacement of [125I]-L-3,5,3’-triiodothyronine from human TRalpha expressed in human Hela cell lysate measured after overnight incubation by competition binding assays	ki	0.0021	uM
2-[4-(4-hydroxy-3-propan-2-ylphenoxy)-3,5-dimethylphenoxy]acetic acid	213173: Binding affinity of compound was determined against Thyroid hormone receptor alpha1	kd	0.0024	uM
2-[[7-(4-hydroxy-3-propan-2-ylphenoxy)-6-methyl-2,3-dihydro-1H-inden-4-yl]amino]-2-oxoacetic acid	664441: Displacement of [125I]T3 from human recombinant thyroid harmone receptor alpha after 16 to 48 hrs by gamma-ray detection	ki	0.0024	uM
4,6-dibromo-5-(4-hydroxy-3-propan-2-ylphenoxy)-1H-indole-2-carboxylic acid	261712: Inhibition of human TR-alpha-1 by radioligand binding assay	ic50	0.0025	uM
3-[4-[(3-propan-2-yl-1H-indol-5-yl)oxy]-3,5-bis(trifluoromethyl)phenyl]propanoic acid	240244: Agonist activity towards thyroid hormone receptor expressed in human HepG2 cells	ec50	0.0026	uM
2-[1-[(4-hydroxy-3-propan-2-ylphenyl)methyl]-3,7-dimethylindol-5-yl]oxyacetic acid	1192348: Displacement of [125I]-L-3,5,3’-triiodothyronine from human TRalpha expressed in human Hela cell lysate measured after overnight incubation by competition binding assays	ki	0.0028	uM
ethyl 2-oxo-2-[4-[(3-propan-2-yl-1H-indol-5-yl)oxy]-3,5-bis(trifluoromethyl)anilino]acetate	240275: Agonist activity towards thyroid hormone receptor expressed in human HepG2 cells	ec50	0.0030	uM
(E)-3-[4-[(3-propan-2-yl-1H-indol-5-yl)oxy]-3,5-bis(trifluoromethyl)phenyl]prop-2-enoic acid	240244: Agonist activity towards thyroid hormone receptor expressed in human HepG2 cells	ec50	0.0032	uM
[4-(4-hydroxy-3-propan-2-ylphenoxy)-3,5-diiodophenoxy]methylphosphonic acid	345695: Displacement of [125I]3,5,3’-triiodo-L-thyronine from His-tagged human recombinant TRalpha1 by scintillation proximity assay	ki	0.0037	uM
ethyl 2-[3,5-dimethyl-4-[(3-propan-2-yl-1H-indol-5-yl)oxy]anilino]-2-oxoacetate	240275: Agonist activity towards thyroid hormone receptor expressed in human HepG2 cells	ec50	0.0040	uM
ethyl 2-[3-chloro-5-methyl-4-[(3-propan-2-yl-1H-indol-5-yl)oxy]anilino]-2-oxoacetate	240275: Agonist activity towards thyroid hormone receptor expressed in human HepG2 cells	ec50	0.0040	uM
methyl 2-[3,5-dichloro-4-[(3-propan-2-yl-1H-indol-5-yl)oxy]anilino]-2-oxoacetate	240275: Agonist activity towards thyroid hormone receptor expressed in human HepG2 cells	ec50	0.0040	uM
4,6-dibromo-5-(4-hydroxy-3-propan-2-ylphenoxy)-2,3-dihydro-1H-indene-2-carboxylic acid	261715: Efficacy against TRAF-alpha-1 reporter cells	ec50	0.0041	uM
3-[4-(5-bromo-6-hydroxynaphthalen-1-yl)-3,5-dichloroanilino]-3-oxopropanoic acid	254851: Inhibitory concentration against cloned human thyroid hormone receptor alpha 1	ic50	0.0043	uM
(2S)-2-[[2-[3,5-dibromo-4-(4-hydroxy-3-propan-2-ylphenoxy)phenyl]acetyl]amino]-3-methylbutanoic acid	1797786: TRalpha-Binding Assay and Thyroid Response Element (TRAFalpha1) Reporter Assay. from Article 10.1016/j.bmcl.2007.05.049: “Thyroid receptor ligands. Part 8: Thyromimetics derived from N-acylated-alpha-amino acid derivatives displaying modulated pharmacological selectivity compared with KB-141.”	ic50	0.0043	uM
2-[3,5-dichloro-4-(4-hydroxy-3-propan-2-ylphenoxy)phenyl]acetic acid	340062: Agonist activity at human thyroid hormone receptor alpha expressed in CV1 cells by TRE-luciferase assay	ec50	0.0045	uM
2-[(1-ethoxy-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl)amino]acetic acid	1910211: Agonist activity at wild type human TR alpha LBD expressed in Escherichia coli BL21 (DE3) assessed as induction of N-terminal biotinylated coactivator SRC2-3 peptide recruitment by alphascreen assay	ec50	0.0048	uM
2-[5-(4-hydroxy-3-propan-2-ylphenoxy)-4,6-dimethyl-2,3-dihydro-1-benzofuran-2-yl]acetic acid	307878: Agonist activity at THR in HepG2 cells by whole cell assay	ec50	0.0051	uM
2-[4-[[4-hydroxy-3-[2-(4-pentylphenyl)ethynyl]-5-propan-2-ylphenyl]methyl]-3,5-dimethylphenoxy]acetic acid	213172: Binding affinity against human Thyroid hormone receptor alpha-1 (hTRalpha1) using radiolabeled T3	kd	0.0052	uM
2-[4-(5-bromo-6-hydroxynaphthalen-1-yl)-3,5-dichloroanilino]-2-oxoacetic acid	254851: Inhibitory concentration against cloned human thyroid hormone receptor alpha 1	ic50	0.0054	uM
(2R)-2-[[2-[3,5-dibromo-4-(4-hydroxy-3-propan-2-ylphenoxy)phenyl]acetyl]amino]-2-phenylacetic acid	1797786: TRalpha-Binding Assay and Thyroid Response Element (TRAFalpha1) Reporter Assay. from Article 10.1016/j.bmcl.2007.05.049: “Thyroid receptor ligands. Part 8: Thyromimetics derived from N-acylated-alpha-amino acid derivatives displaying modulated pharmacological selectivity compared with KB-141.”	ic50	0.0055	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Triiodothyronine	decreases expression, increases secretion, increases activity, increases reaction, increases cleavage (+5 more)	18
tetrabromobisphenol A	affects activity, affects binding, increases activity, decreases reaction	7
bisphenol A	affects binding, decreases reaction, increases activity, decreases methylation, increases expression (+1 more)	5
2,2’,4,4’-tetrabromodiphenyl ether	affects binding, affects reaction, decreases expression, increases abundance	3
Thyroxine	affects binding, increases reaction, increases expression	3
3,3’,5-triiodothyroacetic acid	increases activity, increases reaction, affects binding	2
tetraiodothyroacetic acid	affects binding, increases activity, increases reaction	2
sodium arsenite	increases expression, decreases expression	2
perfluorooctanoic acid	affects binding, decreases activity	2
tetrachlorodian	affects binding, increases activity, decreases reaction	2
perfluorooctane sulfonic acid	affects binding, decreases activity	2
perfluoro-n-nonanoic acid	affects binding, decreases expression	2
bisphenol S	affects binding, decreases reaction, affects cotreatment, increases expression	2
Bortezomib	affects binding, decreases activity, decreases expression, increases response to substance	2
Sunitinib	affects binding, decreases activity, increases expression	2
Vorinostat	affects binding, decreases activity, decreases expression	2
Diethylhexyl Phthalate	affects binding, increases activity, decreases expression	2
Doxorubicin	affects binding, decreases activity, decreases expression	2
Estradiol	increases expression	2
Silicon Dioxide	decreases expression, affects reaction, decreases reaction, increases cleavage, increases expression (+1 more)	2
Tretinoin	decreases expression, increases expression	2
Mifepristone	decreases expression, affects binding, decreases activity	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
GSK-J4	increases expression	1
FR900359	increases phosphorylation	1
bisphenol F	increases expression, affects cotreatment	1
flumetralin	affects binding, increases activity	1
phoxim	affects binding, decreases activity	1
dicloran	affects binding, increases activity	1
N-(2-ethylhexyl)-5-norbornene-2,3-dicarboxamide	affects binding, decreases activity	1

ChEMBL screening assays

140 unique, capped per target: 115 binding, 23 functional, 2 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1015264	Binding	Increase in transcriptional activity of TRalpha ligand binding domain expressed in human Hep G2 cells co-transfected with Gal4-DBD by luciferase reporter gene assay	Crystal structure of the peroxisome proliferator-activated receptor gamma (PPARgamma) ligand binding domain complexed with a novel partial agonist: a new region of the hydrophobic pocket could be exploited for drug design. — J Med Chem
CHEMBL1211360	Functional	Agonist activity at TRalpha-LBD expressed in HEK293 cells assessed as Gal4-DBD interaction by cellular mammalian one hybrid assay	Synthesis and pharmacological validation of a novel series of non-steroidal FXR agonists. — Bioorg Med Chem Lett
CHEMBL4683760	ADMET	Agonist activity at TRalpha (unknown origin) by Lanthascreen TR-FRET assay	Design, synthesis and biological evaluation of novel TRβ selective agonists sustained by ADME-toxicity analysis. — Eur J Med Chem

Cellosaurus cell lines

9 cell lines: 4 cancer cell line, 3 embryonic stem cell, 1 spontaneously immortalized cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A7M3	SEES3-1V human THRA, clone1	Embryonic stem cell	Male
CVCL_A7M4	SEES3-1V human THRA, clone2	Embryonic stem cell	Male
CVCL_A7M5	SEES3-1V human THRA, clone3	Embryonic stem cell	Male
CVCL_C3G9	Hep-G2-THRA	Cancer cell line	Male
CVCL_C3GA	Hep-G2-THRA MUT p.I116N;A225T;M388I	Cancer cell line	Male
CVCL_C3GB	Hep-G2-THRA MUT p.K74E;A264V	Cancer cell line	Male
CVCL_E7G2	Neuro2A[TRa1]	Cancer cell line	Male
CVCL_KZ20	PathHunter CHO-K1 THRalpha Protein Interaction	Spontaneously immortalized cell line	Female
CVCL_LF55	GeneBLAzer TRalpha-UAS-bla HEK 293T	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice