DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for familial glucocorticoid deficiency — screening already-approved drugs against its 30-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleFamilial glucocorticoid deficiency maps to a 30-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 familial glucocorticoid deficiency 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
catechol-O-methyltransferase (COMT) — COMT 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 samdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 5LSA · 1.5 Å · ligand S-ADENOSYLMETHIONINE (SAM). Experimental structure, not a prediction.
What the evidence adds up to
A 2008 study of one family with primary cortisol resistance found that a homozygous G679S mutation in the glucocorticoid receptor-alpha gene caused severe clinical resistance featuring hypertension, hypokalaemia, and hyperandrogenism in three siblings. Heterozygous carriers of the same mutation showed subclinical resistance, but this effect was abolished in those who also carried the ER22/23EK polymorphism, who had normal cortisol suppression after dexamethasone. The sample is a single family of six siblings and two parents, so generalisation is limited.
A 2022 report described two siblings from a consanguineous family with type 1 familial glucocorticoid deficiency caused by a novel homozygous MC2R mutation, c.326T>A (p.Leu109Gln). Both presented with neonatal hypoglycaemia and low cortisol; one also had recurrent infections from two days of age. In vitro work in HEK293 cells showed the mutation disrupted MC2R protein expression and cAMP production after ACTH stimulation. The patients were treated with hydrocortisone replacement. No other drugs were tested.
Two review articles from 2017 and 2019 summarise that familial glucocorticoid deficiency is a rare autosomal recessive disease defined by isolated cortisol deficiency with normal aldosterone and renin. Onset ranges from the neonatal period to adulthood, and clinical features include hypoglycaemia, recurrent infections, hyperpigmentation, and tall stature. The reviews note that diagnosis is difficult and misdiagnosis common because the presentation overlaps with other causes of primary adrenal insufficiency. They list known pathogenic genes but provide no new trial data or treatment outcomes.
What is missing is any controlled trial of drug repurposing for this condition. No abstract reports a drug tested beyond standard hydrocortisone replacement. There is no data on patient stratification by genotype, no funding for a repurposing trial, and no prospective study design that could test whether any existing drug modifies the underlying receptor defect or cAMP signalling failure.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
International Journal of Clinical Practice · 2009 · 25 citations · open access
Is there any relationship between imatinib mesylate medication and hypothalamic-pituitary-adrenal axis dysfunction?
AbstractBACKGROUND: Imatinib mesylate [tyrosine kinase (TK) inhibitor] is a novel medication in the treatment of chronic myelogenous leukaemia (CML). TK is also essential in hypothalamo-pituitary-adrenal (HPA) axis. PURPOSE: The aim of this study was to evaluate HPA axis in patients treated with imatinib. Twenty-five patients were included in this study. METHODS: Glucagon stimulation test (GST) and low-dose (1 microg) adrenocorticotropin test (LDSST) were used to assess the HPA gland axis. RESULTS: Seventeen (68%) subjects had impaired peak response when a cortisol cut-off value is accepted as 500 nmol/L. Twelve (48%) out of 17 subjects also failed to show a response to LDSST. Therefore, 12 patients (48%) were defined as HPA deficient. Only two of these 25 patients had morning serum cortisol < 200 nmol/l (7.22 microg/dl), and failed the GST and/or LDSST, indicating that the majority had partial glucocorticoid deficiency. If the cut-off presume for LDSST is from 500 to 600 nmol/l, 16 patients (64%) would have failed both the GST and LDSST. CONCLUSION: Our results indicate an increased prevalence of subclinical glucocorticoid deficiency in patients receiving imatinib mesylate for CML. Therefore under stressed conditions, such as intercurrent illness state, overt and untreated partial glucocorticoid deficiency in CML patients become life threatening.
European Journal of Endocrinology · 2008 · 24 citations · open access
Genotype–phenotype correlation in a family with primary cortisol resistance: possible modulating effect of the ER22/23EK polymorphism.
AbstractOBJECTIVE: Glucocorticoid resistance is a rare sporadic or familial condition that is characterized by generalized, partial resistance to glucocorticoids. It is caused by a mutation in the glucocorticoid receptor-alpha (GR-alpha) gene. We aimed to understand the reasons for different phenotypes (severe to asymptomatic) observed in a family with primary cortisol resistance. DESIGN: The genotype leading to cortisol resistance in the family members was investigated and correlated to the clinical phenotype. METHOD: Three siblings were presented with clinical cortisol resistance, featuring severe hypertension, hypokalemia and hyperandrogenism. Three other siblings and both parents were asymptomatic. Genomic DNA from peripheral lymphocytes was isolated from family members. The entire GR-alpha coding sequence (exons 2-9) was amplified by PCR and sequenced. RESULTS: A homozygous G679S mutation was present in the three clinically affected subjects. Heterozygous G66A (E22E) and G68A (R23K) polymorphisms and G2035A (G679S) mutation were found in the father and two siblings. Mother and one sibling had only heterozygous G679S mutation. The clinically unaffected subjects showed two different responses to dexamethason. Those with heterozygous G679S mutation and ER22/23EK polymorphism had normal cortisol suppression, whereas those with only heterozygous G679S mutation failed to suppress normally. CONCLUSIONS: A homozygous G679S mutation of the GR-alpha gene is associated with severe cortisol resistance, whereas a heterozygous mutation of the same gene can lead to subclinical cortisol resistance. The effect of the heterozygous mutation was abolished in subjects carrying the ER22/23EK polymorphism.
Journal of the Endocrine Society · 2022 · 9 citations · open access
A Novel Homozygous <i>MC2R</i> Variant Leading to Type-1 Familial Glucocorticoid Deficiency
AbstractContext: Type 1 familial glucocorticoid deficiency (FGD) (OMIM #607397) is a rare autosomal recessive disorder due to mutations in melanocortin-2-receptor (MC2R) gene encoding the G protein-coupled adrenocorticotropic (ACTH) transmembrane receptor. Objective: The aim of the study is to describe 2 siblings born to a healthy consanguineous family presenting with clinical and biochemical features of FGD, harboring a novel homozygous MC2R variant. Methods: Both patients are siblings born at term via normal delivery with normal birth weights. The first sibling presented with symptoms of hypoglycemia, repeated episodes of infections starting from 2 days of age. At 18 months of age, low serum cortisol was found, and he was started on hydrocortisone replacement therapy. The second sibling developed hypoglycemia on day 1 after birth, investigations revealed low serum sodium and cortisol levels and was also commenced on hydrocortisone treatment. Whole exome sequencing (WES) and in vitro functional studies on cell line transfected with wild-type and mutant plasmid clones were undertaken. Results: WES revealed a novel homozygous missense mutation c.326T>A, p.Leu109Gln in the MC2R gene. In-silico prediction tools predicted the effect of this mutation to be deleterious. In vitro study using HEK293 cells transfected with MC2R wild-type and mutant clones showed a defect in protein expression and cAMP generation when stimulated with ACTH. Conclusion: Homozygous semiconserved p.Leu109Gln mutation disrupts cAMP production and MC2R protein expression leading to ACTH resistance. This study provides additional evidence that this novel pathogenic variant in MC2R results in FGD phenotypes.
Hormone Research in Paediatrics · 2025 · 2 citations
Clinical Variability in Congenital Adrenal Hyperplasia: A Distinct Subgroup with A Low Glucocorticoid Dose Requirement
AbstractINTRODUCTION: Some children with classic congenital adrenal hyperplasia (CAH) achieve excellent control on very low glucocorticoid doses. We aimed to characterize these patients and assess the timing of their low-dose requirements. METHODS: We reviewed charts of patients with salt-wasting CAH due to 21-hydroxylase deficiency, defining low-dose glucocorticoid as <10 mg/m2/day. Demographic and growth data were compared with a matched group on standard doses. RESULTS: Among 154 patients with CAH, 14 (9%) required low-dose glucocorticoid therapy (<10 mg/m2/day), including 8 boys (57%) and 6 girls (43%). The average age at treatment initiation was 2.1 years, comparable to a matched group of 23 patients (48% boys). The low-dose group received 8.8 ± 1.2 mg/m2/day versus 14.9 ± 3.9 mg/m2/day in the matched group (p < 0.001), with similar fludrocortisone doses (0.1 ± 0.05 mg). No differences were observed in weight, height, or height velocity. Of the 14 patients on low-dose treatment, 3 experienced an increase in their glucocorticoid dose requirement above 10 mg/m2/day at ages 10.3, 10.8, and 8.5 years after being on 6.3-9.8 mg/m2/day for 6.4-8.5 years. The remaining 11 patients are currently on 5.89-10 mg/m2/day with a duration on low-dose therapy ranging from 0.48 to 8.65 years. CONCLUSION: Our findings highlight a subgroup of patients with 21-hydroxylase deficiency who achieve good control on low glucocorticoid doses from early childhood. The factors underlying this and the transient need for low doses in some remain unclear.
Progress in the study of familial glucocorticoid deficiency
AbstractFamilial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease characterized by a single cortisol deficiency and normal aldosterone and renin levels, reported by Shepard et al. in 1959 for the first time. The onset age of FGD may be early or later, from neonatal to adult. The clinical manifestations vary due to the different age at onset. The clinical identification was difficult and would be prone to misdiagnosis because the disease may have many similarities with primary adrenal insufficiency (PAI) caused by other reasons.
Key words:
Familial glucocorticoid deficiency; Gene mutations
International journal of pediatrics · 2017 · 0 citations
Advances in familial glucocorticoid deficiency
AbstractFamilial glucocorticoid deficiency(FGD) known as one of primary congenital adrenal hypoplasia diseases, is a rare autosomal recessive disorder.FGD is characterised by isolated glucocorticoid deficiency, therefore the patients exhibit low serum cortisol and high plasma adrenocorticotropic hormone levels.The patients typically present with hypoglycemia, recurrent infections, hyperpigmentation and tall stature.Much research on the pathogenic genes and molecular biology mechanisms have been performed, and presently some pathogenic genes have been discovered.In order to enhance the clinicians′understanding of familial glucocorticoid deficiency, this review focuses on the pathogenic genes, pathogenesis, diagnosis and treatments of the disease.
Key words:
Familial glucocorticoid deficiency; Pathogenic genes; Pathogenesis; Treatment
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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