TTR

Summary

TTR (transthyretin, HGNC:12405) is a protein-coding gene on chromosome 18q12.1, encoding Transthyretin (P02766). Thyroid hormone-binding protein.

This gene encodes one of the three prealbumins, which include alpha-1-antitrypsin, transthyretin and orosomucoid. The encoded protein, transthyretin, is a homo-tetrameric carrier protein, which transports thyroid hormones in the plasma and cerebrospinal fluid. It is also involved in the transport of retinol (vitamin A) in the plasma by associating with retinol-binding protein. The protein may also be involved in other intracellular processes including proteolysis, nerve regeneration, autophagy and glucose homeostasis. Mutations in this gene are associated with amyloid deposition, predominantly affecting peripheral nerves or the heart, while a small percentage of the gene mutations are non-amyloidogenic. The mutations are implicated in the etiology of several diseases, including amyloidotic polyneuropathy, euthyroid hyperthyroxinaemia, amyloidotic vitreous opacities, cardiomyopathy, oculoleptomeningeal amyloidosis, meningocerebrovascular amyloidosis and carpal tunnel syndrome.

Source: NCBI Gene 7276 — RefSeq curated summary.

At a glance

• Gene–disease (curated): obsolete hereditary ATTR amyloidosis (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 439 total — 55 pathogenic, 36 likely-pathogenic
• Phenotypes (HPO): 82
• Druggable target: yes — 29 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000371

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12405
Approved symbol	TTR
Name	transthyretin
Location	18q12.1
Locus type	gene with protein product
Status	Approved
Aliases	HsT2651, CTS
Ensembl gene	ENSG00000118271
Ensembl biotype	protein_coding
OMIM	176300
Entrez	7276

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 10 protein_coding, 2 retained_intron

ENST00000237014, ENST00000432547, ENST00000541025, ENST00000610404, ENST00000613781, ENST00000649620, ENST00000676075, ENST00000858988, ENST00000858989, ENST00000858990, ENST00000858991, ENST00000858992

RefSeq mRNA: 1 — MANE Select: NM_000371 NM_000371

CCDS: CCDS11899

Canonical transcript exons

ENST00000237014 — 4 exons

Exon	Start	End
ENSE00000796939	31595120	31595255
ENSE00001827041	31598568	31598821
ENSE00001836564	31591877	31591971
ENSE00003556666	31592896	31593026

Expression profiles

Bgee: expression breadth ubiquitous, 185 present calls, max score 99.99.

FANTOM5 (CAGE): breadth broad, TPM avg 207.2991 / max 68207.5792, expressed in 309 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
169825	207.2795	309
169827	0.0195	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
choroid plexus epithelium	UBERON:0003911	99.99	gold quality
type B pancreatic cell	CL:0000169	99.96	gold quality
right lobe of liver	UBERON:0001114	99.92	gold quality
islet of Langerhans	UBERON:0000006	99.90	gold quality
pigmented layer of retina	UBERON:0001782	99.88	gold quality
liver	UBERON:0002107	99.87	gold quality
body of pancreas	UBERON:0001150	99.28	gold quality
pancreas	UBERON:0001264	98.72	gold quality
adult organism	UBERON:0007023	95.49	gold quality
gall bladder	UBERON:0002110	95.08	gold quality
corpus callosum	UBERON:0002336	89.40	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.47	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	86.96	gold quality
spinal cord	UBERON:0002240	84.73	gold quality
hypothalamus	UBERON:0001898	84.72	gold quality
Ammon’s horn	UBERON:0001954	84.61	gold quality
substantia nigra	UBERON:0002038	82.21	gold quality
colonic epithelium	UBERON:0000397	81.63	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.52	gold quality
body of stomach	UBERON:0001161	81.45	gold quality
olfactory bulb	UBERON:0002264	81.21	gold quality
stomach	UBERON:0000945	81.09	gold quality
epithelial cell of pancreas	CL:0000083	80.90	gold quality
midbrain	UBERON:0001891	80.81	gold quality
fundus of stomach	UBERON:0001160	80.48	gold quality
amygdala	UBERON:0001876	80.16	gold quality
hair follicle	UBERON:0002073	80.15	gold quality
mucosa of urinary bladder	UBERON:0001259	78.76	gold quality
cardia of stomach	UBERON:0001162	78.24	gold quality
medulla oblongata	UBERON:0001896	77.10	gold quality

Single-cell (SCXA)

Detected in 22 experiment(s), a significant marker in 21.

Experiment	Marker?	Max mean expression
E-GEOD-135922	yes	116104.31
E-MTAB-9154	yes	111616.00
E-MTAB-7407	yes	106926.42
E-GEOD-81547	yes	88941.19
E-HCAD-5	yes	78687.30
E-HCAD-31	yes	72160.44
E-ENAD-27	yes	70022.01
E-MTAB-11121	yes	69387.03
E-MTAB-10485	yes	66544.30
E-MTAB-5061	yes	56475.58
E-GEOD-81608	yes	55761.78
E-GEOD-83139	yes	47082.23
E-MTAB-10553	yes	27546.98
E-CURD-98	yes	16960.17
E-MTAB-9906	yes	14043.82

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CEBPA, CLDN19, CLDN3, FOXA1, FOXA2, FOXC1, FOXM1, HNF1A, HNF1B, HNF4A, HSF1, JUN, ONECUT1, SMARCA1

miRNA regulators (miRDB)

37 targeting TTR, 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-513A-5P	100.00	69.77	2465
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-7845-5P	99.88	64.88	771
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-1251-3P	99.64	67.21	1408
HSA-MIR-12117	99.50	67.57	868
HSA-MIR-4696	99.48	67.48	1040
HSA-MIR-130A-5P	99.33	70.26	2623
HSA-MIR-7515	99.31	68.22	1795
HSA-MIR-4796-3P	99.08	68.38	1681
HSA-MIR-7854-3P	99.08	66.26	1117

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• the beta-slip structure and amyloidosis (PMID:11106758)
• structure of a new polymorphic monoclinic form of human transthyretin at 3 A resolution reveals a mixed complex between unliganded and T4-bound tetramers of TTR (PMID:11418763)
• In a model of amyloidogenesis, chemically cross-linked dimeric forms of transthyretin are able to assemble into amyloid fibrils from oligomeric protein building blocks rather than from structurally rearranged monomers. (PMID:11478875)
• incorporation of one or more T119M transthyretin mutant subunits into a predominantly V30M tetramer strongly stabilized the mixed tetramer against dissociation (PMID:11577236)
• Inhibition of transthyretin amyloid fibril formation by 2,4-dinitrophenol through tetramer stabilization (PMID:11913969)
• Structural basis of negative cooperativity in transthyretin (PMID:11995997)
• Transthyretin Val 107 in a Japanese patient with familial amyloid polyneuropathy. point mutation responsible for substitution of valine for isoleucine at position 107 (PMID:12039669)
• DNA analysis showed heterozygosity for normal TTR and the amyloidogenic mutation ATTR (Val30Met) leading to the diagnosis of familial amyloidotic polyneuropathy. (PMID:12082059)
• The correlation between destabilization of the transthyretin core strands and the tendency for amyloid formation(familial amyloid polyneuropathy variants) supports the view that these strands are involved in amyloidogenicity (PMID:12095258)
• role in naso-maxillary deformity in transgenic mice (PMID:12354101)
• The amyloidogenic TTR mutant Y114C exists in three forms: one unstable but nativelike tetrameric form, one highly aggregated form in which a network of disulfide bonds is formed, and one fibrillar form. (PMID:12403615)
• Differences in clinical and geographic features between early- and late-onset familial amyloid polyneuropathy TTR Met30 have been confirmed in Japanese patients with onset before and after 50 years of age. (PMID:12433265)
• TTR(105-115) adopts an extended beta-strand conformation that is similar to that found in the native protein except for substantial differences in the vicinity of the proline residue. (PMID:12481032)
• transthyretin amyloidosis inhibitors functioned by increasing the kinetic barrier associated with misfolding, preventing amyloidogenesis by stabilizing the native state; the trans-suppressor mutation also functioned through kinetic stabilization (PMID:12560553)
• The ATTR Val30 Met and ATTR Tyr114Cys mutations induce different clinical features of vitreous opacities (PMID:12566023)
• Transthyretin intronic open reading frames are not independently expressed in vivo or part of functional transcripts. (PMID:12697331)
• In human muscle, the Val122Ile TTR mutation predisposes to A[beta] deposition and amyloidogenesis and increases presumably toxic intracellular A[beta] oligomers. (PMID:12874414)
• an unidirectional dimer to monomer transition of normal TTR is achieved at 70-80 degrees C in neutral to mild alkaline buffers or at 37 degrees C and slightly acidic pH (6-7). Addition of urea favors the transition into monomers. (PMID:12874858)
• novel pathologic TTR variant with an amino acid substitution (Phe->Cys) at position 33; the Cys33 residue was S-sulfonated and S-thiolated (conjugated to cysteine, cysteinylglycine, and glutathione); these adducts may play a role in TTR fibrillogenesis (PMID:12876326)
• consecutive cycles of compression-decompression under aggregating conditions lead to reversible dissociation of transthyretin and alpha-synuclein fibrils (PMID:12900507)
• Wild-type TTR co-deposits in peripheral nerves with variant TTR as amyloid fibril. Progression of amyloid deposition in peripheral nerves from wild-type TTR may occur after liver transplantation, as has been seen in the heart. (PMID:14506715)
• homocysteine and human plasma transthyretin bind and have roles in the pathological consequences of amyloid disease (PMID:14507924)
• TTR dimers containing amyloidogenic TTR mutations decay into monomers at pH<7.4 (PMID:14534839)
• a novel transthyretin (TTR) variant, aspartic acid-18 glutamic acid (Glu), causing TTR-related cardiac amyloidosis in a heterozygote (PMID:14578606)
• solvent accessibility analysis of transthyretin amyloid by NMR (PMID:14604984)
• genotype-phenotype correlations in familial amyloid polyneuropathy (V30M) in Portugal and Sweden (PMID:14673473)
• Urea-induced unfolding data indicate that amyloidogenic Tyr114His and Tyr116Ser mutations of transthyretin reduce the stability of its secondary, tertiary, and quaternary structure. (PMID:14690414)
• TTR monomers rapidly aggregate to form transient low molecular mass assemblies that are highly cytotoxic in tissue culture. (PMID:14981241)
• TTR can act as a novel plasma cryptic protease and might have a new, potentially important role under physiological and/or pathological conditions. (PMID:15033978)
• The packing of transthyretin molecules in the C2 crystal form and in the previously determined amyloid TTR (ATTR) Leu55Pro crystal structure is close-to-identical (PMID:15210129)
• mutant TTR may have a role in a severe form of amyloidotic polyneuropathy (PMID:15214015)
• Muscular amyloid angiopathy may contribute to motor nerve injury that, in turn, may lead to amyotropic changes in patients with FAP Ser50Ile and Tyr114Cys. (PMID:15536615)
• Serine112isoleucine variant transthyretin exists as a dimer with nonnative tertiary interactions; it self-assembles under nearly physiological conditions into insoluble spherical aggregates that induce cell death in a human neuroblastoma cell line. (PMID:15736938)
• We report a Chinese patient with amyloidotic polyneuropathy associated with a novel transthyretin mutation (V32A)… likely to be associated with late onset and low-penetrance phenotype. (PMID:15793844)
• biophysical analysis of human transthyretin under partially denaturing conditions (PMID:15821170)
• homozygosity for an amyloidogenic transthyretin mutation may have an effect on phenotype and long term outcome in fatal neuropathic amyloidosis (PMID:15930086)
• An Italian family with TTR arg47 mutation whose members (two women and their father) showed a rapid progression of the peripheral nervous system involvement and died within 5 years of clinical onset. (PMID:15995833)
• A patient with familial amyloid polyneuropathy. Gene analysis revealed a heterozygous Glu54Gly substitution (A-to-G change) in the transthyretin gene. (PMID:16053476)
• Mutation in the TTR-amyloid fibril protein is associated with familial amyloid polyneuropathy (PMID:16076613)
• Protein synthesis, including TTR, was reduced in old sheep CP and in newly secreted CSF. These age-related changes suggest reduced capacity of CP to maintain CSF T4 homeostasis and be an added risk for Alzheimer’s disease. (PMID:16079207)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	ttr	ENSDARG00000037191
mus_musculus	Ttr	ENSMUSG00000061808
rattus_norvegicus	Ttr	ENSRNOG00000016275
drosophila_melanogaster	CG30016	FBGN0050016
caenorhabditis_elegans		WBGENE00011181
caenorhabditis_elegans		WBGENE00022808

Paralogs (1): URAD (ENSG00000183463)

Protein

Protein identifiers

Transthyretin — P02766 (reviewed: P02766)

Alternative names: ATTR, Prealbumin, TBPA

All UniProt accessions (4): P02766, A0A087WT59, A0A087WV45, E9KL36

UniProt curated annotations — full annotation on UniProt →

Function. Thyroid hormone-binding protein. Probably transports thyroxine from the bloodstream to the brain.

Subunit / interactions. Homotetramer. Dimer of dimers. In the homotetramer, subunits assemble around a central channel that can accommodate two ligand molecules. Interacts with RBP4.

Subcellular location. Secreted. Cytoplasm.

Tissue specificity. Detected in serum and cerebrospinal fluid (at protein level). Highly expressed in choroid plexus epithelial cells. Detected in retina pigment epithelium and liver.

Post-translational modifications. Not glycosylated under normal conditions. Following unfolding, caused for example by variant AMYLD1 ‘Gly-38’, the cryptic Asn-118 site is exposed and glycosylated by STT3B-containing OST complex, leading to its degradation by the ER-associated degradation (ERAD) pathway. Sulfonation of the reactive cysteine Cys-30 enhances the stability of the native conformation of TTR, avoiding misassembly of the protein leading to amyloid formation.

Disease relevance. Amyloidosis, hereditary systemic 1 (AMYLD1) [MIM:105210] A form of hereditary systemic amyloidosis, a disorder characterized by amyloid deposition in multiple tissues resulting in a wide clinical spectrum. AMYLD1 is an autosomal dominant form due to transthyretin amyloid deposition. Protein fibrils can form in different tissues leading to amyloid polyneuropathies, amyloidotic cardiomyopathy, carpal tunnel syndrome, systemic senile amyloidosis. The disease includes leptomeningeal amyloidosis that is characterized by primary involvement of the central nervous system. Neuropathologic examination shows amyloid in the walls of leptomeningeal vessels, in pia arachnoid, and subpial deposits. Some patients also develop vitreous amyloid deposition that leads to visual impairment (oculoleptomeningeal amyloidosis). Clinical features include seizures, stroke-like episodes, dementia, psychomotor deterioration, variable amyloid deposition in the vitreous humor. The disease is caused by variants affecting the gene represented in this entry. Hyperthyroxinemia, dystransthyretinemic (DTTRH) [MIM:145680] A condition characterized by elevation of total and free thyroxine in healthy, euthyroid persons without detectable binding protein abnormalities. The disease is caused by variants affecting the gene represented in this entry. Carpal tunnel syndrome 1 (CTS1) [MIM:115430] A condition characterized by entrapment of the median nerve within the carpal tunnel. Symptoms include burning pain and paresthesias involving the ventral surface of the hand and fingers which may radiate proximally. Impairment of sensation in the distribution of the median nerve and thenar muscle atrophy may occur. This condition may be associated with repetitive occupational trauma, wrist injuries, amyloid neuropathies, rheumatoid arthritis. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Each monomer has two 4-stranded beta sheets and the shape of a prolate ellipsoid. Antiparallel beta-sheet interactions link monomers into dimers. A short loop from each monomer forms the main dimer-dimer interaction. These two pairs of loops separate the opposed, convex beta-sheets of the dimers to form an internal channel.

Miscellaneous. Tetramer dissociation and partial unfolding leads to the formation of aggregates and amyloid fibrils. Small molecules that occupy at least one of the thyroid hormone binding sites stabilize the tetramer, and thereby stabilize the native state and protect against misfolding and the formation of amyloid fibrils. Two binding sites for thyroxine are located in the channel. Less than 1% of plasma prealbumin molecules are normally involved in thyroxine transport. L-thyroxine binds to the transthyretin by an order of magnitude stronger than does the triiodo-L-thyronine. Thyroxine-binding globulin is the major carrier protein for thyroid hormones in man. About 40% of plasma transthyretin circulates in a tight protein-protein complex with the plasma retinol-binding protein (RBP). The formation of the complex with RBP stabilizes the binding of retinol to RBP and decreases the glomerular filtration and renal catabolism of the relatively small RBP molecule. There is evidence for 2 binding sites for RBP, one possibly being a region that includes Ile-104, located on the outer surface of the transthyretin molecule.

Similarity. Belongs to the transthyretin family.

RefSeq proteins (1): NP_000362* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000895	Transthyretin/HIU_hydrolase	Family
IPR023416	Transthyretin/HIU_hydrolase_d	Domain
IPR023418	Thyroxine_BS	Binding_site
IPR023419	Transthyretin_CS	Conserved_site
IPR036817	Transthyretin/HIU_hydrolase_sf	Homologous_superfamily

Pfam: PF00576

UniProt features (116 total): sequence variant 87, strand 11, turn 4, binding site 3, modified residue 3, mutagenesis site 2, sequence conflict 2, signal peptide 1, chain 1, helix 1, glycosylation site 1

Structure

Experimental structures (PDB)

462 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
1F86	X-RAY DIFFRACTION	1.1
8C86	X-RAY DIFFRACTION	1.1
8W45	X-RAY DIFFRACTION	1.1
4QXV	X-RAY DIFFRACTION	1.12
4KY2	X-RAY DIFFRACTION	1.13
4D7B	X-RAY DIFFRACTION	1.15
7EJQ	X-RAY DIFFRACTION	1.15
8AWI	X-RAY DIFFRACTION	1.15
6TXW	X-RAY DIFFRACTION	1.15
4L1T	X-RAY DIFFRACTION	1.16
4HIQ	X-RAY DIFFRACTION	1.18
9H7L	X-RAY DIFFRACTION	1.18
8C85	X-RAY DIFFRACTION	1.19
7DT3	X-RAY DIFFRACTION	1.2
3M1O	X-RAY DIFFRACTION	1.2
4HIS	X-RAY DIFFRACTION	1.2
5DWP	X-RAY DIFFRACTION	1.2
5FW7	X-RAY DIFFRACTION	1.2
5JID	X-RAY DIFFRACTION	1.2
7QC5	X-RAY DIFFRACTION	1.2
8PMA	X-RAY DIFFRACTION	1.2
6SUG	X-RAY DIFFRACTION	1.21
9H7I	X-RAY DIFFRACTION	1.21
4FI8	X-RAY DIFFRACTION	1.22
4HJS	X-RAY DIFFRACTION	1.22
4MAS	X-RAY DIFFRACTION	1.22
5CLZ	X-RAY DIFFRACTION	1.22
5CM1	X-RAY DIFFRACTION	1.22
4PM1	X-RAY DIFFRACTION	1.23
5CLY	X-RAY DIFFRACTION	1.23

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P02766-F1	88.74	0.79

Antibody-complex structures (SAbDab): 1 — 3BSZ

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 (3): 35; 74; 137

Post-translational modifications (3): 30, 62, 72

Glycosylation sites (1): 118

Mutagenesis-validated functional residues (2):

Position	Phenotype
107	loss of tetramerization; when associated with m-130.
130	loss of tetramerization; when associated with m-107.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-2453902	The canonical retinoid cycle in rods (twilight vision)
R-HSA-3000171	Non-integrin membrane-ECM interactions
R-HSA-6798695	Neutrophil degranulation
R-HSA-975634	Retinoid metabolism and transport
R-HSA-977225	Amyloid fiber formation
R-HSA-9918449	Defective visual phototransduction due to STRA6 loss of function

MSigDB gene sets: 322 (showing top): MODULE_93, REACTOME_INNATE_IMMUNE_SYSTEM, PID_HNF3B_PATHWAY, SASAI_TARGETS_OF_CXCR6_AND_PTCH1_UP, GOCC_SECRETORY_GRANULE, MODULE_445, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, MODULE_404, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, CDP_01, CADWELL_ATG16L1_TARGETS_DN, MODULE_368, chr18q12, FREAC3_01, RGTTAMWNATT_HNF1_01

GO Biological Process (5): retinoid metabolic process (GO:0001523), negative regulation of glomerular filtration (GO:0003105), purine nucleobase metabolic process (GO:0006144), phototransduction, visible light (GO:0007603), signal transduction (GO:0007165)

GO Molecular Function (7): hormone activity (GO:0005179), hormone binding (GO:0042562), identical protein binding (GO:0042802), protein-containing complex binding (GO:0044877), molecular sequestering activity (GO:0140313), protein binding (GO:0005515), thyroid hormone binding (GO:0070324)

GO Cellular Component (6): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), protein-containing complex (GO:0032991), azurophil granule lumen (GO:0035578), extracellular exosome (GO:0070062), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Visual phototransduction	2
Extracellular matrix organization	1
Innate Immune System	1
Metabolism of fat-soluble vitamins	1
Metabolism of proteins	1
Retinoid cycle disease events	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	3
cellular anatomical structure	2
diterpenoid metabolic process	1
regulation of glomerular filtration	1
glomerular filtration	1
negative regulation of multicellular organismal process	1
nucleobase metabolic process	1
purine-containing compound metabolic process	1
phototransduction	1
detection of visible light	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
receptor ligand activity	1
protein binding	1
molecular_function	1
hormone binding	1
cellular_component	1
vacuolar lumen	1
secretory granule lumen	1
azurophil granule	1
extracellular vesicle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

4128 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TTR	RBP4	P02753	997
TTR	ALB	P02768	991
TTR	APOA1	P02647	982
TTR	SERPINA7	P05543	976
TTR	SERPINA1	P01009	954
TTR	B2M	P01884	950
TTR	APP	P05067	907
TTR	LRP2	P98164	904
TTR	APOE	P02649	903
TTR	A2M	P01023	892
TTR	APCS	P02743	887
TTR	HP	P00737	865
TTR	FOXA2	Q9Y261	855
TTR	AFP	P02771	845
TTR	CLU	P10909	833

IntAct

286 interactions, top by confidence:

A	B	Type	Score
TTR	TTR	psi-mi:“MI:0407”(direct interaction)	0.950
TTR	TTR	psi-mi:“MI:0915”(physical association)	0.950
TTR	ATF4	psi-mi:“MI:0915”(physical association)	0.670
OTUB1	TTR	psi-mi:“MI:0915”(physical association)	0.670
RBP4	TTR	psi-mi:“MI:2364”(proximity)	0.650
RBP4	TTR	psi-mi:“MI:0915”(physical association)	0.650
TTR	APP	psi-mi:“MI:0407”(direct interaction)	0.620
APP	TTR	psi-mi:“MI:0407”(direct interaction)	0.620
NECAB2	TTR	psi-mi:“MI:0915”(physical association)	0.560
CDR2	TTR	psi-mi:“MI:0915”(physical association)	0.560
TTR	NECAB2	psi-mi:“MI:0915”(physical association)	0.560
TTR	CDR2	psi-mi:“MI:0915”(physical association)	0.560
TTR	ATF5	psi-mi:“MI:0915”(physical association)	0.560
TTR	NDUFA5	psi-mi:“MI:0915”(physical association)	0.560
ATP6V1B1	TTR	psi-mi:“MI:0915”(physical association)	0.560
KIF1A	TTR	psi-mi:“MI:0915”(physical association)	0.560
KDSR	TTR	psi-mi:“MI:0915”(physical association)	0.560
MNDA	TTR	psi-mi:“MI:0915”(physical association)	0.560
PALM	TTR	psi-mi:“MI:0915”(physical association)	0.560
PIK3R1	TTR	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (114): TTR (Two-hybrid), NECAB2 (Two-hybrid), TTR (Two-hybrid), TTR (Reconstituted Complex), TTR (Affinity Capture-MS), TTR (Affinity Capture-MS), TTR (Affinity Capture-MS), DERL1 (Affinity Capture-Western), DERL2 (Affinity Capture-Western), DERL3 (Affinity Capture-Western), BAG6 (Affinity Capture-Western), VCP (Affinity Capture-Western), SYVN1 (Affinity Capture-Western), TTR (Affinity Capture-MS), RBP4 (Affinity Capture-Luminescence)

ESM2 similar proteins: A4GNA8, A4QNN7, B7ZS96, E2D0Z0, H2KYE0, O44578, O46375, O46654, O49813, O55245, O74492, O82015, P02766, P02767, P07309, P07489, P0C963, P12303, P13447, P19963, P27731, P30623, P31779, P42204, P49141, P49142, P49143, P50390, P55955, Q06S87, Q0IZZ8, Q0Q029, Q21882, Q22288, Q29616, Q29W25, Q5MGQ0, Q5NVS2, Q5U7I5, Q67VU7

Diamond homologs: A4QNN7, B7ZS96, O46375, O46654, O55245, P02766, P02767, P07309, P07489, P12303, P27731, P30623, P31779, P42204, P49141, P49142, P49143, P50390, Q06S87, Q29616, Q5NVS2, Q5U7I5, Q8HXW1, Q9MYN8, O74492, Q8G228, Q8YFU1, Q92UG5, Q9A545, Q21882, Q9CRB3, Q8XXJ7, Q92VB9, P76341, Q8XB75, Q9I3J5, Q9KET9, O32142, O44578, Q4VYA5

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 81 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	7	11.7×	9e-04
Platelet activation, signaling and aggregation	5	10.2×	8e-03
Platelet degranulation	6	10.1×	2e-03
Post-translational protein phosphorylation	5	9.6×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	55
Likely pathogenic	36
Uncertain significance	136
Likely benign	104
Benign	12

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1067500	NM_000371.4(TTR):c.251T>C (p.Phe84Ser)	Pathogenic
1068392	NM_000371.4(TTR):c.186G>C (p.Glu62Asp)	Pathogenic
1075407	NM_000371.4(TTR):c.94C>G (p.Leu32Val)	Pathogenic
1075408	NM_000371.4(TTR):c.182G>T (p.Trp61Leu)	Pathogenic
1178327	NM_000371.4(TTR):c.214T>C (p.Ser72Pro)	Pathogenic
13417	NM_000371.4(TTR):c.148G>A (p.Val50Met)	Pathogenic
13418	NM_000371.4(TTR):c.157T>A (p.Phe53Ile)	Pathogenic
13419	NM_000371.4(TTR):c.401A>G (p.Tyr134Cys)	Pathogenic
13423	NM_000371.4(TTR):c.311T>G (p.Ile104Ser)	Pathogenic
13428	NM_000371.4(TTR):c.185A>G (p.Glu62Gly)	Pathogenic
13429	NM_000371.4(TTR):c.210T>G (p.Ser70Arg)	Pathogenic
13430	NM_000371.4(TTR):c.149T>C (p.Val50Ala)	Pathogenic
13435	NM_000371.4(TTR):c.233T>G (p.Leu78Arg)	Pathogenic
13436	NM_000371.4(TTR):c.199G>C (p.Gly67Arg)	Pathogenic
13437	NM_000371.4(TTR):c.133G>A (p.Ala45Thr)	Pathogenic
13438	NM_000371.4(TTR):c.224T>C (p.Leu75Pro)	Pathogenic
13439	NM_000371.4(TTR):c.209G>T (p.Ser70Ile)	Pathogenic
13440	NM_000371.4(TTR):c.148G>C (p.Val50Leu)	Pathogenic
13441	NM_000371.4(TTR):c.205A>G (p.Thr69Ala)	Pathogenic
13442	NM_000371.4(TTR):c.325G>C (p.Glu109Gln)	Pathogenic
13443	NM_000371.4(TTR):c.270A>C (p.Lys90Asn)	Pathogenic
13448	NM_000371.4(TTR):c.350C>G (p.Ala117Gly)	Pathogenic
13449	NM_000371.4(TTR):c.400T>C (p.Tyr134His)	Pathogenic
13451	NM_000371.4(TTR):c.200G>C (p.Gly67Ala)	Pathogenic
13453	NM_000371.4(TTR):c.250T>C (p.Phe84Leu)	Pathogenic
13455	NM_000371.4(TTR):c.118G>A (p.Val40Ile)	Pathogenic
13456	NM_000371.4(TTR):c.157T>C (p.Phe53Leu)	Pathogenic
13457	NM_000371.4(TTR):c.95T>C (p.Leu32Pro)	Pathogenic
13459	NM_000371.4(TTR):c.199G>A (p.Gly67Arg)	Pathogenic
13460	NM_000371.4(TTR):c.421GTC[1] (p.Val142del)	Pathogenic

SpliceAI

254 predictions. Top by Δscore:

Variant	Effect	Δscore
18:31592888:A:AG	acceptor_gain	1.0000
18:31592889:C:G	acceptor_gain	1.0000
18:31592890:A:AG	acceptor_gain	1.0000
18:31592891:C:G	acceptor_gain	1.0000
18:31592891:CCCA:C	acceptor_loss	1.0000
18:31592892:CCAG:C	acceptor_loss	1.0000
18:31592894:A:AG	acceptor_gain	1.0000
18:31592894:A:T	acceptor_loss	1.0000
18:31592894:AG:A	acceptor_gain	1.0000
18:31592895:G:GG	acceptor_gain	1.0000
18:31592895:GG:G	acceptor_gain	1.0000
18:31592895:GGGC:G	acceptor_gain	1.0000
18:31592895:GGGCA:G	acceptor_gain	1.0000
18:31593022:TCTGG:T	donor_gain	1.0000
18:31593023:CTGG:C	donor_gain	1.0000
18:31593024:TGG:T	donor_gain	1.0000
18:31593024:TGGG:T	donor_loss	1.0000
18:31593025:GG:G	donor_gain	1.0000
18:31593025:GGG:G	donor_gain	1.0000
18:31593025:GGGT:G	donor_loss	1.0000
18:31593026:GG:G	donor_gain	1.0000
18:31593026:GGT:G	donor_loss	1.0000
18:31593027:G:C	donor_loss	1.0000
18:31593027:G:GG	donor_gain	1.0000
18:31593028:T:A	donor_loss	1.0000
18:31595115:TATA:T	acceptor_loss	1.0000
18:31595118:A:AG	acceptor_gain	1.0000
18:31595118:AG:A	acceptor_gain	1.0000
18:31595119:G:GA	acceptor_gain	1.0000
18:31595119:GG:G	acceptor_gain	1.0000

AlphaMissense

942 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:31598625:A:C	S132R	0.996
18:31598627:C:A	S132R	0.996
18:31598627:C:G	S132R	0.996
18:31598575:T:C	F115S	0.995
18:31598634:T:C	S135P	0.990
18:31595137:G:T	G73V	0.987
18:31595137:G:A	G73E	0.986
18:31598574:T:C	F115L	0.986
18:31598576:C:A	F115L	0.986
18:31598576:C:G	F115L	0.986
18:31595184:T:G	Y89D	0.984
18:31598575:T:G	F115C	0.982
18:31598640:T:C	S137P	0.982
18:31593009:G:C	W61C	0.981
18:31593009:G:T	W61C	0.981
18:31595238:T:C	F107L	0.981
18:31595240:C:A	F107L	0.981
18:31595240:C:G	F107L	0.981
18:31598650:C:A	A140D	0.981
18:31598611:T:A	I127N	0.980
18:31592960:C:A	A45D	0.978
18:31595214:T:A	W99R	0.978
18:31595214:T:C	W99R	0.978
18:31595216:G:C	W99C	0.977
18:31595216:G:T	W99C	0.977
18:31592938:G:C	D38H	0.976
18:31592927:T:A	V34D	0.973
18:31592951:G:T	G42V	0.973
18:31592950:G:C	G42R	0.971
18:31593007:T:A	W61R	0.971

dbSNP variants (sampled 300 via entrez): RS1000095380 (18:31598940 A>G), RS1000152341 (18:31591829 T>A), RS1000179628 (18:31593510 T>C), RS1000492164 (18:31593641 A>G,T), RS1000563547 (18:31593862 A>G), RS1000784925 (18:31595024 A>G,T), RS1000846091 (18:31596393 T>G), RS1001593868 (18:31590884 A>C), RS1001610481 (18:31590451 T>C), RS1001677771 (18:31597322 G>A,C,T), RS1002014970 (18:31595985 C>T), RS1003081847 (18:31594024 T>C), RS1003111298 (18:31594230 G>C), RS1003531132 (18:31592558 C>T), RS1003894359 (18:31598937 G>A,T)

Disease associations

OMIM: gene MIM:176300 | disease phenotypes: MIM:105210, MIM:145680, MIM:115430, MIM:118220, MIM:192600, MIM:601144, MIM:115080

GenCC curated gene-disease

Disease	Classification	Inheritance
familial amyloid neuropathy	Definitive	Autosomal dominant
amyloidosis, hereditary systemic 1	Definitive	Autosomal dominant
heart conduction disease	Strong	Autosomal dominant
carpal tunnel syndrome 1	Strong	Autosomal dominant
ATTRV122I amyloidosis	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
obsolete hereditary ATTR amyloidosis	Definitive	AD

Mondo (19): amyloidosis, hereditary systemic 1 (MONDO:0971004), cardiomyopathy (MONDO:0004994), hyperthyroxinemia, dystransthyretinemic (MONDO:0007785), carpal tunnel syndrome 1 (MONDO:0020730), amyloidosis (MONDO:0019065), Charcot-Marie-Tooth disease (MONDO:0015626), ATTRV122I amyloidosis (MONDO:0019441), heart failure (MONDO:0005252), hyperthyroidism (MONDO:0004425), hereditary amyloidosis (MONDO:0018634), hypertrophic cardiomyopathy (MONDO:0005045), carpal tunnel syndrome (MONDO:0007275), myocarditis (MONDO:0004496), acute myocardial infarction (MONDO:0004781), familial hypertrophic cardiomyopathy (MONDO:0024573)

Orphanet (12): ATTRV30M amyloidosis (Orphanet:85447), ATTRV122I amyloidosis (Orphanet:85451), Rare cardiomyopathy (Orphanet:167848), Amyloidosis (Orphanet:69), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), Hereditary amyloidosis (Orphanet:444116), Rare hypertrophic cardiomyopathy (Orphanet:217569), Rare familial disorder with hypertrophic cardiomyopathy (Orphanet:99739), Brugada syndrome (Orphanet:130), Hereditary progressive cardiac conduction defect (Orphanet:871), NON RARE IN EUROPE: Carpal tunnel syndrome (Orphanet:50838), NON RARE IN EUROPE: Familial isolated hypertrophic cardiomyopathy (Orphanet:155)

HPO phenotypes

82 total (30 of 82 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000020	Urinary incontinence
HP:0000112	Nephropathy
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000639	Nystagmus
HP:0000651	Diplopia
HP:0000666	Horizontal nystagmus
HP:0000726	Dementia
HP:0000738	Hallucinations
HP:0000739	Anxiety
HP:0000802	Impotence
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001265	Hyporeflexia
HP:0001269	Hemiparesis
HP:0001271	Polyneuropathy
HP:0001289	Confusion
HP:0001297	Stroke
HP:0001324	Muscle weakness
HP:0001337	Tremor
HP:0001347	Hyperreflexia
HP:0001635	Congestive heart failure
HP:0001638	Cardiomyopathy
HP:0001639	Hypertrophic cardiomyopathy
HP:0001640	Cardiomegaly

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST001216_2	Retinol levels	6.000000e-14

MeSH disease descriptors (13)

Descriptor	Name	Tree numbers
D000686	Amyloidosis	C18.452.845.500
D028226	Amyloidosis, Familial	C16.320.565.176; C18.452.648.176; C18.452.845.500.075
D053840	Brugada Syndrome	C14.280.067.322; C14.280.123.250; C16.320.100
D009202	Cardiomyopathies	C14.280.238
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160
D024741	Cardiomyopathy, Hypertrophic, Familial	C14.280.238.100.500; C14.280.484.048.750.070.160.500; C16.320.160
D002349	Carpal Tunnel Syndrome	C10.668.829.500.500.200; C10.668.829.550.200; C26.844.150.206
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
D006333	Heart Failure	C14.280.434
D006980	Hyperthyroidism	C19.874.397
D009205	Myocarditis	C14.280.238.625
C567782	Amyloidosis, Hereditary, Transthyretin-Related (supp.)
C567719	Dystransthyretinemic Euthyroidal Hyperthyroxinemia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3194 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

29 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 588,260 (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
CHEMBL1086440	TRICLABENDAZOLE	4	4,136
CHEMBL1096	AMLEXANOX	4	4,195
CHEMBL1324	TOLCAPONE	4	13,819
CHEMBL139	DICLOFENAC	4	125,009
CHEMBL1624	LEVOTHYROXINE	4	81,643
CHEMBL2103837	TAFAMIDIS	4	672
CHEMBL232201	BENZIODARONE	4	1,341
CHEMBL290106	BITHIONOL	4	6,439
CHEMBL388590	BENZBROMARONE	4	8,245
CHEMBL3940890	ACORAMIDIS	4	576
CHEMBL457	GEMFIBROZIL	4	35,238
CHEMBL509	MECLOFENAMIC ACID	4	45,809
CHEMBL5416410	DASATINIB	4	655
CHEMBL559	DEXTROTHYROXINE	4	3,634
CHEMBL849	TRICLOSAN	4	77,720
CHEMBL898	DIFLUNISAL	4	54,786
CHEMBL145	CAFFEIC ACID	3	36,305
CHEMBL165	RESVERATROL	3	60,144
CHEMBL297453	EPIGALOCATECHIN GALLATE	3	22,804
CHEMBL41286	DIACEREIN	3	5,090
CHEMBL121626	TOLFENAMIC ACID	2
CHEMBL151	LUTEOLIN	2
CHEMBL23588	FLUFENAMIC ACID	2
CHEMBL253896	XANTHOHUMOL	2
CHEMBL44	GENISTEIN	2
CHEMBL63323	NIFLUMIC ACID	2
CHEMBL8145	DAIDZEIN	2
CHEMBL83527	PTEROSTILBENE	2
CHEMBL93645	ACECLOFENAC	2

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs28933979	TTR		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: other protein — Transthyretin

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
tafamidis	Binding	8.7	pKd
acoramidis	Binding	8.32	pKd
apigenin	Binding	6.6	pKd

Binding affinities (BindingDB)

152 measured of 153 human assays (154 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
[6-(cyclopropylmethyl)-1,4,5,7-tetrahydropyrazolo[5,4-c]pyridin-3-yl]-[4-[3-fluoro-2-(trifluoromethyl)phenyl]piperidin-1-yl]methanone	IC50	4.35 nM	US-9434727: Substituted 4-phenylpiperidines, their preparation and use
3-[4-(2-chloro-3-fluorophenyl)piperidine-1-carbonyl]-1,4,5,7-tetrahydropyrazolo[5,4-c]pyridine-6-carbonitrile	IC50	5.12 nM	US-10072016: Substituted 4-phenylpiperidines, their preparation and use
3-[4-[2-fluoro-6-(trifluoromethyl)phenyl]piperidine-1-carbonyl]-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile	IC50	5.84 nM	US-10072016: Substituted 4-phenylpiperidines, their preparation and use
[4-(2-chloro-5-fluorophenyl)piperidin-1-yl]-(5-methylsulfonyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl)methanone	IC50	6.17 nM	US-10072016: Substituted 4-phenylpiperidines, their preparation and use
3-[4-[3-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carbonyl]-N-methyl-1,4,5,7-tetrahydropyrazolo[5,4-c]pyridine-6-carboxamide	IC50	7.5 nM	US-9434727: Substituted 4-phenylpiperidines, their preparation and use
[5-(cyclopropylmethyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-[4-[3-fluoro-2-(trifluoromethyl)phenyl]piperidin-1-yl]methanone	IC50	10 nM	US-10072016: Substituted 4-phenylpiperidines, their preparation and use
methyl 3-[4-[3,5-difluoro-2-(trifluoromethyl)phenyl]piperidine-1-carbonyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate	IC50	10.1 nM	US-10072016: Substituted 4-phenylpiperidines, their preparation and use
3-[4-[3,4-difluoro-2-(trifluoromethyl)phenyl]piperidine-1-carbonyl]-N-methyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide	IC50	10.2 nM	US-10072016: Substituted 4-phenylpiperidines, their preparation and use
[4-(2-chloro-3-fluorophenyl)piperidin-1-yl]-(5-methylsulfonyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl)methanone	IC50	10.3 nM	US-9434727: Substituted 4-phenylpiperidines, their preparation and use
3-[4-[3-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carbonyl]-N-methyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide	IC50	10.3 nM	US-9434727: Substituted 4-phenylpiperidines, their preparation and use
3-[4-[3,5-difluoro-2-(trifluoromethyl)phenyl]piperidine-1-carbonyl]-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile	IC50	10.5 nM	US-9434727: Substituted 4-phenylpiperidines, their preparation and use
[4-[3-fluoro-2-(trifluoromethyl)phenyl]piperidin-1-yl]-[6-(2-methoxyethyl)-1,4,5,7-tetrahydropyrazolo[5,4-c]pyridin-3-yl]methanone	IC50	10.6 nM	US-9434727: Substituted 4-phenylpiperidines, their preparation and use
3-[4-[3-chloro-2-(trifluoromethyl)phenyl]piperidine-1-carbonyl]-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile	IC50	10.7 nM	US-9434727: Substituted 4-phenylpiperidines, their preparation and use
[4-[3,4-difluoro-2-(trifluoromethyl)phenyl]piperidin-1-yl]-[6-(3,3,3-trifluoropropyl)-1,4,5,7-tetrahydropyrazolo[5,4-c]pyridin-3-yl]methanone	IC50	10.7 nM	US-10072016: Substituted 4-phenylpiperidines, their preparation and use
[4-[3-fluoro-2-(trifluoromethyl)phenyl]piperidin-1-yl]-[5-(3,3,3-trifluoropropyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]methanone	IC50	10.8 nM	US-9434727: Substituted 4-phenylpiperidines, their preparation and use
[4-[3,4-difluoro-2-(trifluoromethyl)phenyl]piperidin-1-yl]-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone	IC50	10.9 nM	US-9434727: Substituted 4-phenylpiperidines, their preparation and use
1-[3-[4-[3,5-difluoro-2-(trifluoromethyl)phenyl]piperidine-1-carbonyl]-1,4,5,7-tetrahydropyrazolo[5,4-c]pyridin-6-yl]ethanone	IC50	10.9 nM	US-9434727: Substituted 4-phenylpiperidines, their preparation and use
[4-[3,4-difluoro-2-(trifluoromethyl)phenyl]piperidin-1-yl]-[5-(pyridine-4-carbonyl)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrazol-3-yl]methanone	IC50	11.2 nM	US-9434727: Substituted 4-phenylpiperidines, their preparation and use
methyl 3-[4-[3,4-difluoro-2-(trifluoromethyl)phenyl]piperidine-1-carbonyl]-1,4,5,7-tetrahydropyrazolo[5,4-c]pyridine-6-carboxylate	IC50	11.4 nM	US-10072016: Substituted 4-phenylpiperidines, their preparation and use
3-[4-[3,4-difluoro-2-(trifluoromethyl)phenyl]piperidine-1-carbonyl]-N-methyl-1,4,5,7-tetrahydropyrazolo[5,4-c]pyridine-6-carboxamide	IC50	11.5 nM	US-9434727: Substituted 4-phenylpiperidines, their preparation and use
[4-[3-fluoro-2-(trifluoromethyl)phenyl]piperidin-1-yl]-[5-(oxetan-3-yl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]methanone	IC50	11.6 nM	US-9434727: Substituted 4-phenylpiperidines, their preparation and use
1-[3-[4-[3,4-difluoro-2-(trifluoromethyl)phenyl]piperidine-1-carbonyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl]ethanone	IC50	11.6 nM	US-10072016: Substituted 4-phenylpiperidines, their preparation and use
1-[3-[4-[3,4-difluoro-2-(trifluoromethyl)phenyl]piperidine-1-carbonyl]-4,6-dihydro-1H-pyrrolo[3,4-d]pyrazol-5-yl]ethanone	IC50	11.6 nM	US-10072016: Substituted 4-phenylpiperidines, their preparation and use
[4-(2-chloro-3-fluorophenyl)piperidin-1-yl]-[5-(3,3,3-trifluoropropyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]methanone	IC50	11.7 nM	US-10072016: Substituted 4-phenylpiperidines, their preparation and use
[4-[3,4-difluoro-2-(trifluoromethyl)phenyl]piperidin-1-yl]-[5-(oxetan-3-yl)-4,6-dihydro-1H-pyrrolo[3,4-d]pyrazol-3-yl]methanone	IC50	11.8 nM	US-10072016: Substituted 4-phenylpiperidines, their preparation and use
3-[4-[3,5-difluoro-2-(trifluoromethyl)phenyl]piperidine-1-carbonyl]-1,4,5,7-tetrahydropyrazolo[5,4-c]pyridine-6-carbonitrile	IC50	12 nM	US-9434727: Substituted 4-phenylpiperidines, their preparation and use
[4-(2-chloro-3-fluorophenyl)piperidin-1-yl]-[5-(2,2,2-trifluoroethyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]methanone	IC50	12.2 nM	US-9434727: Substituted 4-phenylpiperidines, their preparation and use
[4-[3,4-difluoro-2-(trifluoromethyl)phenyl]piperidin-1-yl]-(5-ethyl-4,6-dihydro-1H-pyrrolo[3,4-d]pyrazol-3-yl)methanone	IC50	12.7 nM	US-9434727: Substituted 4-phenylpiperidines, their preparation and use
3-[4-[3-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carbonyl]-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile	IC50	12.7 nM	US-9434727: Substituted 4-phenylpiperidines, their preparation and use
methyl 3-[4-[3,5-difluoro-2-(trifluoromethyl)phenyl]piperidine-1-carbonyl]-1,4,5,7-tetrahydropyrazolo[5,4-c]pyridine-6-carboxylate	IC50	12.8 nM	US-10072016: Substituted 4-phenylpiperidines, their preparation and use
[4-[3-fluoro-2-(trifluoromethyl)phenyl]piperidin-1-yl]-(4,5,6,7-tetrahydro-1H-pyrazolo[5,4-c]pyridin-3-yl)methanone	IC50	13.3 nM	US-10072016: Substituted 4-phenylpiperidines, their preparation and use
[5-(cyclopropylmethyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-[4-[3,4-difluoro-2-(trifluoromethyl)phenyl]piperidin-1-yl]methanone	IC50	13.4 nM	US-10072016: Substituted 4-phenylpiperidines, their preparation and use
[4-(2-chloro-3-fluorophenyl)piperidin-1-yl]-[5-(cyclopropylmethyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]methanone	IC50	13.6 nM	US-9434727: Substituted 4-phenylpiperidines, their preparation and use
[4-[3,5-difluoro-2-(trifluoromethyl)phenyl]piperidin-1-yl]-[5-(3,3,3-trifluoropropyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]methanone	IC50	13.8 nM	US-9434727: Substituted 4-phenylpiperidines, their preparation and use
1-[3-[4-[3,4-difluoro-2-(trifluoromethyl)phenyl]piperidine-1-carbonyl]-1,4,5,7-tetrahydropyrazolo[5,4-c]pyridin-6-yl]ethanone	IC50	13.9 nM	US-9434727: Substituted 4-phenylpiperidines, their preparation and use
[4-(2-chloro-3-fluorophenyl)piperidin-1-yl]-(4,5,6,7-tetrahydro-1H-pyrazolo[5,4-c]pyridin-3-yl)methanone	IC50	14 nM	US-10072016: Substituted 4-phenylpiperidines, their preparation and use
methyl 3-[4-[3,4-difluoro-2-(trifluoromethyl)phenyl]piperidine-1-carbonyl]-4,6-dihydro-1H-pyrrolo[3,4-d]pyrazole-5-carboxylate	IC50	14.1 nM	US-9434727: Substituted 4-phenylpiperidines, their preparation and use
[6-(cyclopropylmethyl)-1,4,5,7-tetrahydropyrazolo[5,4-c]pyridin-3-yl]-[4-[3,4-difluoro-2-(trifluoromethyl)phenyl]piperidin-1-yl]methanone	IC50	14.2 nM	US-9434727: Substituted 4-phenylpiperidines, their preparation and use
[5-(cyclopropylmethyl)-4,6-dihydro-1H-pyrrolo[3,4-d]pyrazol-3-yl]-[4-[3,4-difluoro-2-(trifluoromethyl)phenyl]piperidin-1-yl]methanone	IC50	14.3 nM	US-10072016: Substituted 4-phenylpiperidines, their preparation and use
[4-[3,4-difluoro-2-(trifluoromethyl)phenyl]piperidin-1-yl]-[5-(2,2-dimethylpropyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]methanone	IC50	14.4 nM	US-9434727: Substituted 4-phenylpiperidines, their preparation and use
[4-[3,4-difluoro-2-(trifluoromethyl)phenyl]piperidin-1-yl]-[6-(2-methoxyethyl)-1,4,5,7-tetrahydropyrazolo[5,4-c]pyridin-3-yl]methanone	IC50	14.6 nM	US-10072016: Substituted 4-phenylpiperidines, their preparation and use
1-[3-[4-[3,4-difluoro-2-(trifluoromethyl)phenyl]piperidine-1-carbonyl]-4,6-dihydro-1H-pyrrolo[3,4-d]pyrazol-5-yl]propan-1-one	IC50	14.7 nM	US-9434727: Substituted 4-phenylpiperidines, their preparation and use
[4-[3,4-difluoro-2-(trifluoromethyl)phenyl]piperidin-1-yl]-[5-(2-methoxyethyl)-4,6-dihydro-1H-pyrrolo[3,4-d]pyrazol-3-yl]methanone	IC50	14.9 nM	US-10072016: Substituted 4-phenylpiperidines, their preparation and use
[4-[3,4-difluoro-2-(trifluoromethyl)phenyl]piperidin-1-yl]-[6-(2,2,2-trifluoroethyl)-1,4,5,7-tetrahydropyrazolo[5,4-c]pyridin-3-yl]methanone	IC50	15 nM	US-9434727: Substituted 4-phenylpiperidines, their preparation and use
1-[3-[4-[3,4-difluoro-2-(trifluoromethyl)phenyl]piperidine-1-carbonyl]-1,4,5,7-tetrahydropyrazolo[5,4-c]pyridin-6-yl]-3-methylbutan-1-one	IC50	15.1 nM	US-9434727: Substituted 4-phenylpiperidines, their preparation and use
[4-(2-chloro-3-fluorophenyl)piperidin-1-yl]-(5-ethyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl)methanone	IC50	15.3 nM	US-9434727: Substituted 4-phenylpiperidines, their preparation and use
3-[4-[3,4-difluoro-2-(trifluoromethyl)phenyl]piperidine-1-carbonyl]-4,6-dihydro-1H-pyrrolo[3,4-d]pyrazole-5-carbonitrile	IC50	15.4 nM	US-9434727: Substituted 4-phenylpiperidines, their preparation and use
[4-(2-chloro-3-fluorophenyl)piperidin-1-yl]-[5-(2-methoxyethyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]methanone	IC50	15.5 nM	US-10072016: Substituted 4-phenylpiperidines, their preparation and use
[4-(2-chloro-3-fluorophenyl)piperidin-1-yl]-[5-(oxetan-3-yl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]methanone	IC50	15.6 nM	US-9434727: Substituted 4-phenylpiperidines, their preparation and use
[4-[3-fluoro-2-(trifluoromethyl)phenyl]piperidin-1-yl]-[6-(oxetan-3-yl)-1,4,5,7-tetrahydropyrazolo[5,4-c]pyridin-3-yl]methanone	IC50	15.8 nM	US-9434727: Substituted 4-phenylpiperidines, their preparation and use

ChEMBL bioactivities

375 potent at pChembl≥5 of 461 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.70	Kd	0.2	nM	CHEMBL438498
9.52	Kd	0.3	nM	CHEMBL240806
8.57	EC50	2.7	nM	TAFAMIDIS
8.52	Kd	3	nM	TAFAMIDIS
8.46	Kd	3.5	nM	CHEMBL3959466
8.41	Kd	3.9	nM	CHEMBL3890392
8.36	Kd	4.4	nM	TAFAMIDIS
8.32	Kd	4.8	nM	ACORAMIDIS
8.24	Kd	5.7	nM	CHEMBL240805
8.22	Kd	6	nM	CHEMBL5276223
8.21	Kd	6.2	nM	CHEMBL5203058
8.14	Kd	7.3	nM	ACORAMIDIS
8.03	Kd	9.3	nM	TAFAMIDIS
8.00	Kd	9.9	nM	TAFAMIDIS
7.89	Kd	13	nM	CHEMBL5268339
7.86	Kd	13.9	nM	CHEMBL240804
7.85	Kd	14	nM	CHEMBL5408344
7.85	Kd	14	nM	IOXYNIL
7.82	Kd	15	nM	BENZBROMARONE
7.80	Kd	16	nM	CHEMBL5283388
7.80	Kd	16	nM	CHEMBL5408344
7.69	Kd	20.6	nM	TOLCAPONE
7.58	Kd	26	nM	CHEMBL5172990
7.58	Kd	26	nM	CHEMBL5280970
7.57	Kd	27	nM	CHEMBL241454
7.57	Kd	27	nM	CHEMBL240808
7.52	Kd	30	nM	FLUFENAMIC ACID
7.51	Kd	31	nM	CHEMBL5172066
7.47	Kd	34	nM	TOLCAPONE
7.44	Kd	36	nM	CHEMBL5408344
7.44	Kd	36	nM	TAFAMIDIS
7.40	Kd	40	nM	CHEMBL5575152
7.38	Kd	42	nM	CHEMBL240165
7.38	Kd	42	nM	CHEMBL5570538
7.32	Kd	48	nM	TOLCAPONE
7.30	Kd	50	nM	TOLCAPONE
7.28	Kd	53	nM	CHEMBL5573622
7.25	Kd	56	nM	TOLCAPONE
7.22	Kd	60	nM	DICLOFENAC
7.21	Kd	62	nM	BITHIONOL
7.18	Kd	66	nM	CHEMBL5566935
7.16	Kd	70	nM	LUTEOLIN
7.14	Kd	72.5	nM	CHEMBL122055
7.13	Kd	74.3	nM	CHEMBL5205181
7.12	Kd	75	nM	DIFLUNISAL
7.11	Kd	78	nM	BENZIODARONE
7.11	Kd	77	nM	BROMOXYNIL
7.07	Kd	85	nM	CHEMBL5205412
7.06	Kd	88	nM	CHEMBL241453
7.05	Kd	90	nM	CHEMBL4206443

PubChem BioAssay actives

282 with measured affinity, of 2937 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
4-(chloromethyl)-2-methoxy-1-phenoxybenzene	303083: Binding affinity to transthyretin at pH 4.4	kd	<0.0001	uM
4-(2,4-dichlorophenoxy)-3-methoxybenzoic acid	303083: Binding affinity to transthyretin at pH 4.4	kd	0.0002	uM
2-(2,4-dichlorophenoxy)-5-(hydroxymethyl)phenol	303083: Binding affinity to transthyretin at pH 4.4	kd	0.0003	uM
Tafamidis	1979327: Inhibition of wild type TTR (unknown origin)	ec50	0.0027	uM
5-[(E)-2-(5-chlorofuran-2-yl)ethenyl]-4-methylfuran-3-carboxylic acid	1322956: Binding affinity to recombinant human wild type TTR expressed in Escherichia coli BL21 (DE3) assessed as dissociation constants for first binding site of TTR by isothermal titration calorimetric method	kd	0.0035	uM
5-[(E)-2-(5-chlorofuran-2-yl)ethenyl]-2-methylfuran-3-carboxylic acid	1322956: Binding affinity to recombinant human wild type TTR expressed in Escherichia coli BL21 (DE3) assessed as dissociation constants for first binding site of TTR by isothermal titration calorimetric method	kd	0.0039	uM
Acoramidis	1322958: Binding affinity to human plasma wild type TTR assessed as dissociation constants for second binding site of TTR by isothermal titration calorimetric method	kd	0.0048	uM
5-(chloromethyl)-2-(2,4-dichlorophenoxy)phenol	303083: Binding affinity to transthyretin at pH 4.4	kd	0.0057	uM
2-(3,5-dichlorophenyl)-5,7-dihydroxy-2,3-dihydrochromen-4-one	1936190: Binding affinity to TTR V30M mutant (unknown origin) expressed in Escherichia coli by ITC assay	kd	0.0060	uM
(3,4-dihydroxy-5-nitrophenyl)-(3-fluoro-5-hydroxyphenyl)methanone	1848638: Binding affinity to wild type TTR (unknown origin) assessed as dissociation constant by ITC assay	kd	0.0062	uM
2-(3,5-dichloro-4-hydroxyphenyl)-5-hydroxy-2,3-dihydrochromen-4-one	1936190: Binding affinity to TTR V30M mutant (unknown origin) expressed in Escherichia coli by ITC assay	kd	0.0130	uM
4-(2,4-dichlorophenoxy)-3-hydroxybenzaldehyde	303083: Binding affinity to transthyretin at pH 4.4	kd	0.0139	uM
(3-fluoro-5-hydroxyphenyl)-(4-hydroxy-3-methoxy-5-nitrophenyl)methanone	1983976: Binding affinity to TTR V122I mutant (unknown origin) expressed in Escherichia coli BL21(DE3) assessed as dissociation constant by ITC analysis	kd	0.0140	uM
2-(3,5-dichloro-4-hydroxyphenyl)-5,7-dihydroxy-2,3-dihydrochromen-4-one	1936190: Binding affinity to TTR V30M mutant (unknown origin) expressed in Escherichia coli by ITC assay	kd	0.0160	uM
Tolcapone	1386000: Binding affinity to transthyretin (unknown origin) by ITC method	kd	0.0206	uM
(3,5-difluorophenyl)-(3,4-dihydroxy-5-nitrophenyl)methanone	1848638: Binding affinity to wild type TTR (unknown origin) assessed as dissociation constant by ITC assay	kd	0.0260	uM
2-(3,5-dichloro-4-hydroxyphenyl)-7-hydroxy-2,3-dihydrochromen-4-one	1936190: Binding affinity to TTR V30M mutant (unknown origin) expressed in Escherichia coli by ITC assay	kd	0.0260	uM
3-hydroxy-4-phenoxybenzoic acid	303083: Binding affinity to transthyretin at pH 4.4	kd	0.0270	uM
4-(2,4-dichlorophenoxy)-3-hydroxybenzoic acid	303083: Binding affinity to transthyretin at pH 4.4	kd	0.0270	uM
2-[3-(trifluoromethyl)anilino]benzoic acid	1705462: Binding affinity to wild type TTR (unknown origin) expressed in Escherichia coli BL21/DE3 by Circular dichroism spectroscopy	kd	0.0300	uM
(3,4-dihydroxy-5-nitrophenyl)-(4-fluorophenyl)methanone	1848638: Binding affinity to wild type TTR (unknown origin) assessed as dissociation constant by ITC assay	kd	0.0310	uM
(4-bromo-2-ethyl-1-benzofuran-3-yl)-(4-hydroxy-3,5-diiodophenyl)methanone	2106218: Binding affinity to TTR V30M mutant (unknown origin) assessed as dissociation constant by ITC analysis	kd	0.0400	uM
(2-ethyl-4-methyl-1-benzofuran-3-yl)-(4-hydroxy-3,5-diiodophenyl)methanone	2106218: Binding affinity to TTR V30M mutant (unknown origin) assessed as dissociation constant by ITC analysis	kd	0.0420	uM
5-(2-hydroxyphenyl)-3H-1,3,4-oxadiazole-2-thione	303083: Binding affinity to transthyretin at pH 4.4	kd	0.0420	uM
(4,7-dichloro-2-ethyl-1-benzofuran-3-yl)-(4-hydroxy-3,5-diiodophenyl)methanone	2106218: Binding affinity to TTR V30M mutant (unknown origin) assessed as dissociation constant by ITC analysis	kd	0.0530	uM
Diclofenac	1705462: Binding affinity to wild type TTR (unknown origin) expressed in Escherichia coli BL21/DE3 by Circular dichroism spectroscopy	kd	0.0600	uM
2,4-dichloro-6-(3,5-dichloro-2-hydroxyphenyl)sulfanylphenol	1774086: Binding affinity to TTR V30M mutant (unknown origin) by isothermal titration calorimetry	kd	0.0620	uM
(4-chloro-2-ethyl-1-benzofuran-3-yl)-(4-hydroxy-3,5-diiodophenyl)methanone	2106218: Binding affinity to TTR V30M mutant (unknown origin) assessed as dissociation constant by ITC analysis	kd	0.0660	uM
2-(3,4-dihydroxyphenyl)-5,7-dihydroxychromen-4-one	1239060: Binding affinity to TTR (unknown origin) by isothermal titration calorimetric analysis	kd	0.0700	uM
3-[6-[2-[2-(2-azidoethoxy)ethoxy]ethylamino]hexoxy]-5-[3-(3,5-dimethyl-1H-pyrazol-4-yl)propoxy]benzoic acid	1896523: Binding affinity to human TTR incubated for 20 mins by fluorescence polarization assay	kd	0.0743	uM
Diflunisal	1705462: Binding affinity to wild type TTR (unknown origin) expressed in Escherichia coli BL21/DE3 by Circular dichroism spectroscopy	kd	0.0750	uM
(2-ethyl-1-benzofuran-3-yl)-(4-hydroxy-3,5-diiodophenyl)methanone	2106218: Binding affinity to TTR V30M mutant (unknown origin) assessed as dissociation constant by ITC analysis	kd	0.0780	uM
(3,5-dichlorophenyl)-(3,4-dihydroxy-5-nitrophenyl)methanone	1848638: Binding affinity to wild type TTR (unknown origin) assessed as dissociation constant by ITC assay	kd	0.0850	uM
3-methoxy-4-phenoxybenzaldehyde	303083: Binding affinity to transthyretin at pH 4.4	kd	0.0880	uM
3-[3-(3,5-dimethyl-1H-pyrazol-4-yl)propoxy]-4-iodobenzoic acid	1386000: Binding affinity to transthyretin (unknown origin) by ITC method	kd	0.0900	uM
Gemfibrozil	1239060: Binding affinity to TTR (unknown origin) by isothermal titration calorimetric analysis	kd	0.1000	uM
(2-ethyl-4-iodo-1-benzofuran-3-yl)-(4-hydroxy-3,5-diiodophenyl)methanone	2106218: Binding affinity to TTR V30M mutant (unknown origin) assessed as dissociation constant by ITC analysis	kd	0.1200	uM
2,3,6-trichloro-N-(1H-1,2,4-triazol-5-yl)benzamide	303083: Binding affinity to transthyretin at pH 4.4	kd	0.1200	uM
2-(3-chloro-2-methylanilino)benzoic acid	1239060: Binding affinity to TTR (unknown origin) by isothermal titration calorimetric analysis	kd	0.1500	uM
3-[4-(3,5-dimethyl-1H-pyrazol-4-yl)piperazin-1-yl]-4-iodobenzoic acid	1810837: Binding affinity to human plasma TTR tetramer assessed as displacement of diclofenac-coupled FITC by fluorescence polarization assay	ic50	0.1900	uM
4-chloro-3-[4-(3,5-dimethyl-1H-pyrazol-4-yl)piperazin-1-yl]benzoic acid	1810837: Binding affinity to human plasma TTR tetramer assessed as displacement of diclofenac-coupled FITC by fluorescence polarization assay	ic50	0.2000	uM
(3,5-dibromo-4-hydroxyphenyl)-(2-ethyl-1-benzofuran-3-yl)methanone	1974888: Binding affinity to thyroxin binding site of TTR V30M mutant (unknown origin) expressed in Escherichia coli assessed as quenching of intrinsic tryptophan fluorescence by measuring apparent dissociation constant incubated for 60 mins by fluorescence based analysis	kd	0.2000	uM
3-[4-(3,5-dimethyl-1H-pyrazol-4-yl)piperazin-1-yl]-4-methylbenzoic acid	1810837: Binding affinity to human plasma TTR tetramer assessed as displacement of diclofenac-coupled FITC by fluorescence polarization assay	ic50	0.2100	uM
3-[4-(3,5-dimethyl-1H-pyrazol-4-yl)piperazin-1-yl]-4-fluorobenzoic acid	1810837: Binding affinity to human plasma TTR tetramer assessed as displacement of diclofenac-coupled FITC by fluorescence polarization assay	ic50	0.2200	uM
5,7-dihydroxy-2-(4-hydroxyphenyl)chromen-4-one	1239060: Binding affinity to TTR (unknown origin) by isothermal titration calorimetric analysis	kd	0.2500	uM
4-fluoro-3-[3-(1,3,5-trimethylpyrazol-4-yl)propoxy]benzoic acid	1386000: Binding affinity to transthyretin (unknown origin) by ITC method	kd	0.2510	uM
methyl 3-[3-(3,5-dimethyl-1H-pyrazol-4-yl)propoxy]-4-fluorobenzoate	1386000: Binding affinity to transthyretin (unknown origin) by ITC method	kd	0.2580	uM
3-[4-(3,5-dimethyl-1H-pyrazol-4-yl)piperazin-1-yl]-4-(trifluoromethyl)benzoic acid	1810837: Binding affinity to human plasma TTR tetramer assessed as displacement of diclofenac-coupled FITC by fluorescence polarization assay	ic50	0.2600	uM
1-(3,5-dimethyl-1H-pyrazol-4-yl)-4-[2-fluoro-5-(2H-tetrazol-5-yl)phenyl]piperazine	1810837: Binding affinity to human plasma TTR tetramer assessed as displacement of diclofenac-coupled FITC by fluorescence polarization assay	ic50	0.2600	uM
2-[3-(trifluoromethyl)anilino]pyridine-3-carboxylic acid	1239060: Binding affinity to TTR (unknown origin) by isothermal titration calorimetric analysis	kd	0.2600	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Thyroxine	affects binding, decreases reaction, affects reaction	15
tetrabromobisphenol A	affects binding, decreases reaction, increases stability	6
bisphenol A	affects binding, decreases reaction, affects expression	5
perfluorooctanoic acid	affects reaction, decreases reaction, affects binding	3
tetrachlorodian	affects binding, decreases reaction	3
perfluorooctane sulfonic acid	decreases reaction, affects binding, affects reaction	3
Benzo(a)pyrene	decreases expression, increases expression, increases methylation, affects methylation	3
Cadmium	increases palmitoylation, decreases expression, affects binding, decreases reaction, increases abundance	3
Cyclosporine	decreases expression	3
sodium arsenite	decreases expression, increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
pentabromophenol	affects binding, decreases reaction	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	2
perfluorohexanoic acid	affects binding, affects reaction, decreases reaction	2
2,2’,4,4’-tetrabromodiphenyl ether	affects binding, decreases reaction	2
perfluorobutanesulfonic acid	affects binding, affects reaction, decreases reaction	2
tafamidis	affects binding, increases reaction, increases stability	2
Copper	affects binding, affects reaction	2
Diflunisal	affects binding, decreases response to substance, increases stability	2
Flame Retardants	affects binding, decreases reaction	2
Phenylmercuric Acetate	increases expression, affects cotreatment	2
Triiodothyronine	affects binding	2
Valproic Acid	decreases expression, decreases methylation	2
Zinc	affects binding, affects reaction	2
Aflatoxin B1	affects expression, decreases methylation	2
Halogenated Diphenyl Ethers	affects binding, decreases reaction	2
ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate	affects binding, decreases reaction	1
2,4,6-tribromophenol	affects binding	1
methylmercuric chloride	increases expression	1
propionaldehyde	decreases expression	1

ChEMBL screening assays

423 unique, capped per target: 391 binding, 32 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1027431	Binding	Inhibition of wild type-TTR expressed in Escherichia coli assessed as amyloid fibril formation at pH 4.4 at 7. 2 uM after 72 hrs by acid-mediated aggregation assay relative to control	Toward optimization of the linker substructure common to transthyretin amyloidogenesis inhibitors using biochemical and structural studies. — J Med Chem
CHEMBL3562000	Functional	PubChem BioAssay. Luminescence-based cell-based high throughput dose response assay to identify activators of Transthyretin (TTR) transcription. (Class of assay: confirmatory)	PubChem BioAssay data set

Cellosaurus cell lines

9 cell lines: 9 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A9T3	PUMCHi005-A	Induced pluripotent stem cell	Male
CVCL_C1SD	SCVIi066-A	Induced pluripotent stem cell	Male
CVCL_C1SE	SCVIi067-A	Induced pluripotent stem cell	Male
CVCL_C9E5	ESi107-A	Induced pluripotent stem cell	Female
CVCL_D0LB	SCVIi091-A	Induced pluripotent stem cell	Female
CVCL_D0LC	SCVIi092-A	Induced pluripotent stem cell	Female
CVCL_D2WJ	ATTR3	Induced pluripotent stem cell	Male
CVCL_D2WK	ATTR5	Induced pluripotent stem cell	Male
CVCL_ZX53	PUMCHi004-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00277563	PHASE4	COMPLETED	Short and Long Term Exposure to Unique, Time-Varying Pulsed Electro-Magnetic Fields in Refractory Carpal Tunnel Syndrome
NCT00678314	PHASE4	COMPLETED	Patient Controlled Regional Analgesia Following Carpal Tunnel Release: A Double-Blind Study Using Distal Perineural Catheters
NCT00904202	PHASE4	COMPLETED	A Study Of Lidocaine Patch 5% Alone, Gabapentin Alone, And Lidocaine Patch 5% And Gabapentin In Combination For The Relief Of Pain In Patients With Diverse Peripheral Neuropathic Pain Conditions
NCT01310218	PHASE4	COMPLETED	Length of Post Operative Dressing After Carpal Tunnel Release
NCT01588158	PHASE4	TERMINATED	Patient Satisfaction With Pain Relief After Ambulatory Hand Surgery
NCT01751347	PHASE4	COMPLETED	Bupivacaine Versus Lidocaine Local Anesthesia
NCT02038452	PHASE4	COMPLETED	Injection Versus Splinting in Carpal Tunnel Syndrome
NCT02140632	PHASE4	COMPLETED	Efficacy Study of Local Steroid Injection and Wrist Splinting for Carpal Tunnel Syndrome
NCT02652390	PHASE4	COMPLETED	Local Steroid Injection vs Placebo in Carpal Tunnel Syndrome
NCT03196817	PHASE4	UNKNOWN	Non-surgical Treatment of Carpal Tunnel Syndrome: Night Splint Versus Local Corticosteroid Infiltration
NCT03432858	PHASE4	COMPLETED	Preoperative Antibiotics for Carpal Tunnel Release Surgery
NCT03649763	PHASE4	COMPLETED	Onset and Duration of Forearm Nerve Blockade
NCT03792945	PHASE4	COMPLETED	Comparison of the Efficacy of Corticosteroid Injection and ESWT in Patients With CTS
NCT03802448	PHASE4	COMPLETED	Myofascial Release on Electrophysiological Measures of Pregnant Women With CTS
NCT03867539	PHASE4	RECRUITING	Exparel and Education to Avoid Opioids After Carpal Tunnel Release
NCT04017390	PHASE4	WITHDRAWN	The Effect of Theraworx Foam in Carpal Tunnel Syndrome
NCT04025203	PHASE4	COMPLETED	Pain Reduction and Changes in Upper Limb Function Produced by Different Treatments in Carpal Tunnel Syndrome
NCT04119739	PHASE4	COMPLETED	Pain Reduction Produced by Different Treatments in Carpal Tunnel Syndrome
NCT04245371	PHASE4	COMPLETED	Lidocaine Patch 1.8% for Moderate to Severe Pain From Carpal Tunnel Syndrome
NCT04285281	PHASE4	COMPLETED	Oral Gabapentin and Median Nerve Mobilization in the Treatment of Carpal Tunnel Syndrome
NCT04328805	PHASE4	COMPLETED	Ibuprofen and Neural Mobilization Treatment in Carpal Tunnel Syndrome.
NCT04460521	PHASE4	RECRUITING	The ACTS Trial: N-acetylcysteine (NAC) and Night-splinting as a Non-operative Treatment for Carpal Tunnel Syndrome
NCT04515966	PHASE4	UNKNOWN	A Comparison of Ultrasound-guided Steroid Injection With Wrist Splint in Carpal Tunnel Syndrome
NCT04767724	PHASE4	COMPLETED	Extracorporeal Shock Wave Versus Local Corticosteroid Injection for Carpal Tunnel Syndrome
NCT05306548	PHASE4	ACTIVE_NOT_RECRUITING	A Norwegian Trial Comparing Treatment Strategies for Carpal Tunnel Syndrome
NCT05475808	PHASE4	ACTIVE_NOT_RECRUITING	Comparison of the Efficacy of Different Treatment Methods in Patients With Carpal Tunnel Syndrome
NCT05496764	PHASE4	UNKNOWN	Local Injection of Steroid VS.Glucose 5% in Carpal Tunnel Syndrome
NCT06209957	PHASE4	COMPLETED	Study of Single Platelet-Rich Plasma Local Injection Vs. Single Corticosteroid Local Injection in Carpal Tunnel Syndrome
NCT06249503	PHASE4	COMPLETED	Ultrasound Guided Activated and Non Activated Platelet Rich Plasma Injection Versus Hydro Dissection by Steroids.
NCT06282640	PHASE4	COMPLETED	Comparıson Of Electromyography Results Before And After Vıtamın D Treatment In Patıents Wıth Carpal Tunnel Syndrome
NCT06349265	PHASE4	COMPLETED	Ultrasound-Guided 5% Dextrose Injection for Carpal Tunnel Syndrome
NCT06349824	PHASE4	COMPLETED	Dextrose, Steroid, PRP: Choosing the Right Injection for CRS Relief; a RCT
NCT06778759	PHASE4	COMPLETED	Ibuprofen Arginine and Neural Mobilization Versus Ibuprofen Arginine in the Treatment of Carpal Tunnel Syndrome
NCT06778798	PHASE4	COMPLETED	Gabapentin and Neural Mobilization Pain Reduction Effect Compared to Only Gabapentine
NCT06781489	PHASE4	COMPLETED	Pain Reduction Caused by the Combined Treatment of Physiotherapy, Oral Gabapentin and Oral Ibuprofen Arginine.
NCT07105540	PHASE4	COMPLETED	Comparison of Injection Techniques in Carpal Tunnel Syndrome
NCT07283874	PHASE4	NOT_YET_RECRUITING	Does it Matter the Volume of Injectate on the Outcome of Ultrasound-guided Perineural Injection for Carpal Tunnel Syndrome
NCT00348530	PHASE4	UNKNOWN	Carvedilol Versus Verapamil in Chronic Heart Failure Secondary to Non-Ischemic Cardiomyopathy
NCT00371891	PHASE4	COMPLETED	Ontario Multidetector Computed Tomographic (MDCT) Coronary Angiography Study (OMCAS)
NCT00401856	PHASE4	COMPLETED	CMR to Assess Fibrosis in Cardiomyopathy Using Eplerenone