DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for thyroid hormone resistance syndrome — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleThyroid hormone resistance syndrome maps to a 2-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for thyroid hormone resistance syndrome is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
thyroid hormone receptor alpha (THRA) — THRA is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet 1-methylethyldrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3ILZ · 1.85 Å · ligand {4-[4-hydroxy-3-(1-methylethyl)benzyl]-3,5-dimethylphenoxy}acetic acid (B72). Experimental structure, not a prediction.
What the evidence adds up to
Resistance to thyroid hormone is usually dominantly inherited and defined by elevated free thyroid hormones in serum alongside failure to suppress pituitary TSH secretion, with variable tissue refractoriness. Two major forms are recognised: generalised resistance (GRTH), often asymptomatic, and predominant pituitary resistance (PRTH), with thyrotoxic features. Both are associated with diverse mutations in the thyroid hormone receptor beta gene, localising to three regions in the hormone binding domain. Mutant receptors are functionally impaired and inhibit wild-type receptors in a dominant negative manner. Recognised features include failure to thrive, growth retardation, attention-deficit hyperactivity disorder in childhood, and goitre with thyrotoxic cardiac symptoms in adults. The pathogenesis of variable tissue resistance is not fully understood but may relate to differing tissue distributions of alpha and beta receptors and variable dominant negative activity on different target genes.
A 2009 report described a 16-year-old male with generalised resistance and a novel nonsense mutation in codon 449 of the TR beta gene, producing a receptor 13 amino acids deficient at the carboxy-terminus. Resistance was mild: the patient was eumetabolic despite elevated free thyroid hormones, and both thyrotrope and peripheral tissues responded to triiodothyronine administration. This contrasts with two previously reported cases of severe resistance from truncations of 16 or 11 amino acids at the C-terminus, indicating that truncation length does not uniformly determine severity.
In the past three years up to 2016, 15 patients with resistance to thyroid hormone alpha (RTHα) and nine THRA gene mutations had been reported, reforming the classification of RTH. RTHα presents distinct clinical manifestations from RTHβ, including growth retardation, skeletal dysplasia, impaired neurodevelopment, cardiovascular dysfunction, constipation, and a specific thyroid axis type. Clinical features and effects of L-T4 treatment correlate strongly with mutation severity, mostly within the domain governing TR interaction with T3 and its corepressors or coactivators. Diagnosis clues and promising treatment are proposed, but no controlled trial data are provided.
Mutations in the thyrotropin-receptor gene cause a separate resistance syndrome—thyrotropin resistance—resulting in hypothyroidism, distinct from thyroid hormone resistance caused by mutations in the thyroid hormone receptor beta gene. What remains missing for both RTHα and RTHβ are prospective clinical trials with standardised outcome measures, larger patient cohorts to stratify by mutation type and tissue-specific resistance, and funding for long-term follow-up of treatments such as L-T4 in RTHα.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Physiological Reviews · 2001 · 2011 citations
Physiological and Molecular Basis of Thyroid Hormone Action
AbstractThyroid hormones (THs) play critical roles in the differentiation, growth, metabolism, and physiological function of virtually all tissues. TH binds to receptors that are ligand-regulatable transcription factors belonging to the nuclear hormone receptor superfamily. Tremendous progress has been made recently in our understanding of the molecular mechanisms that underlie TH action. In this review, we present the major advances in our knowledge of the molecular mechanisms of TH action and their implications for TH action in specific tissues, resistance to thyroid hormone syndrome, and genetically engineered mouse models.
New England Journal of Medicine · 1995 · 347 citations · open access
Resistance to Thyrotropin Caused by Mutations in the Thyrotropin-Receptor Gene
AbstractHormone-resistance syndromes can be broadly defined as conditions resulting from reduced or absent end-organ responsiveness to biologically active hormones. They are caused by defects in hormone receptors or post-receptor defects.1–3 Mutations in the thyroid hormone–receptor β gene cause resistance to thyroid hormone, which is characterized by elevated serum thyroid hormone concentrations with few or no clinical and biochemical manifestations of thyroid hormone excess and, most notably, normal or slightly increased thyrotropin secretion.1 Mutations that inactivate the thyrotropin receptor or the G (guanine nucleotide–binding) protein that couples the receptor to adenylate cyclase should cause thyrotropin resistance, resulting in either hypothyroidism . . .
AbstractResistance to thyroid hormone (RTH) is usually dominantly inherited and is characterized by elevated free thyroid hormones in the serum and failure to suppress pituitary thyroid stimulating hormone (TSH) secretion with variable refractoriness to hormone action in peripheral tissues. Two major forms of the disorder are recognized: asymptomatic individuals with generalized resistance (GRTH) and patients with thyrotoxic features, suggesting predominant pituitary resistance (PRTH). Molecular genetic analyses indicate that both GRTH and PRTH are associated with diverse mutations in the thyroid hormone receptor beta gene, which localize to three regions in the hormone binding domain of the receptor. In addition to being functionally impaired, the mutant receptors are also able to inhibit their wild-type counterparts in a dominant negative manner. Recognized features of RTH include failure to thrive, growth retardation and attention-deficit hyperactivity disorder in childhood, and goitre and thyrotoxic cardiac symptoms in adults. The pathogenesis of variable tissue resistance is not fully understood but may be related to the differing tissue distributions of a and b thyroid hormone receptors and variable dominant negative activity of mutant receptors on different target genes.
Journal of Pediatric Endocrinology and Metabolism · 2016 · 11 citations
Resistance to thyroid hormone α, revelation of basic study to clinical consequences
AbstractIn the past 3 years, 15 patients with resistance to thyroid hormone α (RTHα), nine THRA gene mutations have been reported, reforming classification of RTH. RTHα exhibits distinguished clinical manifestations from RTHβ, including growth retardation, skeletal dysplasia, impaired neurodevelopment, cardiovascular dysfunction, constipation and specific thyroid axis type. This review focuses on possible pathogenesis by revelatory basic science of RTHα animal models in vivo, and patients' mutant thyroid hormone receptor α (TRα) in vitro. Clinical manifestations and L-T4 effects are summarized, showing strong correlation to the severity of mutation mostly within the domain which dominated TR interaction with T3 and its corepressors/coactivators. In particular, we propose the diagnosis clues and promising treatment for clinicians.
Mild resistance to thyroid hormone with a truncated thyroid hormone receptor ß
AbstractRecent studies have revealed mutations in the thyroid hormone receptor beta (TR beta) gene as a cause of the most cases of the thyroid hormone resistance syndrome. We have identified a novel nonsense mutation in codon 449 in the 3' end of exon 10 in the TR beta gene in a 16-year-old male patient with generalized resistance to thyroid hormone who also had familial thyroxine binding globulin deficiency. Receptor protein generated from this gene is thought to be 13 amino acid deficient at carboxy-terminus. Resistance to thyroid hormone was mild at least when the patient was evaluated. The patient was eumetabolic in the presence of elevated plasma-free thyroid hormone levels, and both thyrotrope and peripheral tissues responded to triiodothyronine (T3) administration. This mildness of resistance is in contrast to severe resistance to thyroid hormone in two previously reported cases with truncated receptors in which 16 amino acids or 11 amino acids were deficient at C-terminus. Thus, truncation of C-terminus of thyroid hormone receptor beta does not uniformly produce sever resistance.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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