DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for Cushing syndrome — screening already-approved drugs against its 10-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleCushing syndrome maps to a 10-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
Structures already discussed alongside cushing syndrome in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
RU486 — Mifepristone has a real, experimentally solved structure in complex with this target (PDB 2W8Y, 1.8 Å). This is the drug's own deposited structure, not a prediction, and confirms it is a structurally characterised molecule rather than an untested guess.
Loading structure…
helix sheet 486drag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 2W8Y · 1.8 Å · ligand Mifepristone (486). Experimental structure, not a prediction.
What the evidence adds up to
Six consecutive patients with Cushing’s disease were treated with ketoconazole. Urinary cortisol fell to within the normal range in five of the six. One patient developed acute hypoadrenalism, three had nausea and pyrexia, and three showed reversible hepatotoxicity within 7 to 12 days. The authors concluded that further work is required before ketoconazole can be recommended as standard primary therapy. A later stereoisomer, levoketoconazole, was investigated in a phase III SONICS study and normalised cortisol levels and improved cardiovascular risk biomarkers in a significant percentage of patients, with improvements in clinician-rated signs, patient-reported quality of life, and depression severity; testosterone fell significantly in women. The safety profile was described as acceptable with no unexpected signals. Fluconazole was reported in a single case as an alternative when ketoconazole caused intolerable pruritus and skin exfoliation; combined with cabergoline, it produced stable disease control for 15 months in one patient with recurrent Cushing’s disease.
Mifepristone, a glucocorticoid receptor antagonist, was approved by the US FDA in 2012 for controlling hyperglycaemia in Cushing’s syndrome patients who are not surgical candidates or have not achieved remission from surgery. In its pivotal trial, 60% of patients responded with significant improvements in glycaemic control and 38% had a reduction in diastolic blood pressure. The most common adverse events were nausea, fatigue, headache, endometrial hyperplasia, and hypokalaemia; adrenal insufficiency occurred in fewer than 5% of patients. A review noted that about half of treated patients experienced a reduction in elevated blood pressure and half of diabetic patients improved blood glucose levels, but blockade of glucocorticoid receptors leads to increased ACTH and cortisol, making it difficult to diagnose adrenal deficiency and risking severe hypokalaemia. The same review stated that the lack of a large prospective cohort and scarcity of long-term data do not allow recommending mifepristone as first-line therapy. A separate case series of five women with Cushing’s disease and central hypothyroidism found that mifepristone initiation was associated with a fall in free thyroxine, requiring a median 1.83-fold increase in levothyroxine dose; weight loss occurred in four of five patients (3.2 to 42.6 kg over up to 54 months). Another report noted that reversal of clinical features occurs in close to 90% of patients refractory to other treatments, but serum cortisol may rise during treatment, complicating the picture before pituitary adenectomy.
A selective glucocorticoid receptor antagonist, CORT125134, was identified as a clinical candidate and is being evaluated in a phase 2 study in patients with Cushing’s syndrome, aiming to avoid the unwanted side effects of mifepristone’s lack of receptor selectivity.
What remains missing are large, prospective, long-term cohorts for mifepristone, phase III data for levoketoconazole beyond the single SONICS study, and any comparative trials between these drugs. No agent has been tested against surgery in a randomised design, and patient stratification by aetiology, prior treatment, or metabolic phenotype has not been established. Funding for such trials, and for the development of selective GR antagonists, is still needed.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Clinical Endocrinology · 1987 · 81 citations
CLINICAL EXPERIENCE WITH KETOCONAZOLE AS A THERAPY FOR PATIENTS WITH CUSHING'S SYNDROME
AbstractSix consecutive patients with Cushing's disease were treated with the broad spectrum antifungal drug ketoconazole. Urinary cortisol levels rapidly fell to within the normal range in five of the six patients. Acute hypoadrenalism occurred in one patient, and nausea and pyrexia in three. Our experience with hepatotoxicity was different from that reported by others in that reversible hepatotoxicity was demonstrated in three patients within 7 to 12 days of treatment. Further work is required before ketoconazole can be recommended as a standard primary therapy for patients with Cushing's syndrome. Continuing vigilance for both hypoadrenalism and hepatotoxicity is essential in any patient being treated with this drug either for hypercortisolism or for other reasons.
Neuroendocrinology · 2010 · 64 citations · open access
Medical Treatment of Cushing’s Syndrome: Glucocorticoid Receptor Antagonists and Mifepristone
AbstractMifepristone is the first and only available glucocorticoid receptor antagonist. It was initially mainly considered as a so-called 'contragestive' pill due to its antiprogestin activity. In this review, we summarize the results of mifepristone reported in the literature as a treatment of Cushing's syndrome. Most of the patients were treated due to unsuccessful surgery and/or partially effective anticortisolic drugs. The majority of them presented a rapid decrease of clinical signs of hypercortisolism during the first month of treatment; about half experienced a reduction in their elevated blood pressure, and half of the diabetic patients presented improved blood glucose levels. Mifepristone treatment has 2 main drawbacks: (1) the blockade of glucocorticoid receptors leads to increased ACTH and cortisol levels, making it difficult to adapt the treatment and diagnose adrenal deficiency, and (2) increased cortisol levels can also lead to severe hypokalemia. Follow-up of efficacy should only be clinical (weight, blood pressure, skin lesions) and biological (regular blood potassium sampling). Dose adjustment will be performed based on these parameters. The lack of a large available prospective cohort of patients on mifepristone, and the scarcity of data on its long-term effects, does not allow recommending it as a first-line drug in the treatment of hypercortisolism. However, as mifepristone is a rapidly effective drug, it can play a role in the management of hypercortisolism. The main indication is the partial efficacy or bad tolerance of other well-known anticortisolic drugs, either by replacement (bad tolerance, lack of effectiveness) or addition (multimodal approach) of mifepristone.
Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · 2013 · 54 citations
Mifepristone for Management of <scp>C</scp> ushing's Syndrome
AbstractCushing's syndrome is a debilitating endocrine disorder caused by elevated circulating glucocorticoid levels. Although uncommon, Cushing's syndrome is associated with significant morbidity necessitating rapid reversal of hypercortisolemia. Primary therapy for most patients with Cushing's syndrome is surgical, but many patients will require additional treatments with radiation or drugs. Although several options for drug therapy exist, few are readily available and all have dose-limiting adverse effects. Mifepristone (RU 486), a first-in-class glucocorticoid receptor antagonist, was approved by the United States Food and Drug Administration in 2012 for use in Cushing's syndrome to control hyperglycemia in patients who are not surgical candidates or have not achieved remission from surgery. The drug is approved for oral once-daily administration. In its pivotal trial, 60% of patients responded to mifepristone with significant improvements in glycemic control and 38% had a reduction in diastolic blood pressure. The most common adverse events were nausea, fatigue, headache, endometrial hyperplasia, and hypokalemia. Adrenal insufficiency occurred in fewer than 5% of patients. The recommended starting dosage of mifepristone is 300 mg/day. The dosage may be increased every 2-4 weeks up to a maximum of 1200 mg/day, although it should not exceed 20 mg/kg/day. Significant drug-drug interactions exist due to mifepristone's effects on a number of cytochrome P450 enzymes. Despite its limitations, mifepristone is a welcome addition and an appropriate alternative to the available drug therapy for Cushing's syndrome.
Expert Review of Endocrinology & Metabolism · 2021 · 16 citations · open access
Levoketoconazole: a novel treatment for endogenous Cushing's syndrome
AbstractIntroduction: Endogenous Cushing’s syndrome (CS) is a rare, life-threatening endocrine disorder that is caused by chronic exposure to cortisol overproduction. Levoketoconazole (Recorlev), a 2S, 4R stereoisomer of ketoconazole, is a steroidogenesis inhibitor under investigation for the treatment of CS.Areas covered: This review covers the pharmacology, efficacy, and safety of levoketoconazole for the treatment of patients with endogenous CS.Expert opinion: Based on the preclinical and clinical pharmacology findings, levoketoconazole appears to be the relevant enantiomer of ketoconazole for inhibition of steroidogenesis, with more potent inhibition of both cortisol and androgen synthesis relative to ketoconazole racemate and the 2R, 4S stereoisomer dextroketoconazole. Results from the phase III SONICS study showed that levoketoconazole was effective in normalizing cortisol levels and improving biomarkers of cardiovascular risk in a significant percentage of patients. In addition, treatment with levoketoconazole showed improvements in subjective clinical assessments of clinician-rated CS clinical signs and symptoms, patient-reported quality of life, and depression symptom severity. Testosterone levels decreased significantly in women. Levoketoconazole had an acceptable safety profile with no unexpected safety signals. The favorable pharmacology, efficacy, and safety profile of levoketoconazole supports its use as medical therapy for CS, if approved.
Journal of the Endocrine Society · 2019 · 13 citations · open access
Mifepristone Increases Thyroid Hormone Requirements in Patients With Central Hypothyroidism: A Multicenter Study
AbstractPURPOSE: Mifepristone is a glucocorticoid and progesterone receptor blocker that can be used for patients with hyperglycemia and Cushing syndrome in whom surgery failed to achieve remission or who were ineligible for surgery. We report a case series of patients with Cushing disease (CD) and central hypothyroidism that presented with increased levothyroxine requirements during mifepristone therapy. METHODS: Retrospective longitudinal case series of patients with CD and central hypothyroidism treated with mifepristone in a retrospective database at four pituitary centers in the United States. RESULTS: Five patients with CD were found, all women, median age 50 (interquartile range 47 to 64.5). They received mifepristone because no adequate response or intolerance to other drugs was observed. Mifepristone initiation was associated with a decrease in free thyroxine levels, mandating a dose increase of a median 1.83 (1.71 to 3.5) times the initial dose of levothyroxine to achieve normal levels. Weight loss was seen in four of five patients, ranging from 3.2 to 42.6 kg in up to 54 months of follow-up. CONCLUSIONS: Although the mechanism behind the decrease in thyroid hormone level is unknown, intestinal malabsorption, decreased residual thyroid function and increased inactivation of T4 via deiodinases are all potential causes. Whereas therapies for hypercortisolism aim to decrease features of hypercortisolemia such as weight gain and depression, hypothyroidism can hamper these goals. This case series raises awareness on the importance of assessment of thyroid status in patients receiving mifepristone to optimize clinical outcomes.
Fluconazole as a Safe and Effective Alternative to Ketoconazole in Controlling Hypercortisolism of Recurrent Cushing’s Disease: A Case Report
AbstractINTRODUCTION: Ketoconazole has long been the first-line medical therapy for controlling hypercortisolism secondary to either pituitary or adrenal pathology. However, it is largely unavailable in most countries. As a result, we have turned to fluconazole as a viable alternative in view of its favourable safety profile. CASE PRESENTATION: A 50-year-old lady developed recurrent Cushing's disease after being in remission following transsphenoidal surgery (TSS) for a left pituitary microadenoma 16 years ago. The repeat MRI showed a right pituitary microadenoma (1.7 mm × 1.3 mm) for which she underwent a second TSS. However, she continued to have persistent hypercortisolism despite repeated MRIs showing absence of tumour recurrence. She refused bilateral adrenalectomy and external radiotherapy. Ketoconazole was commenced at 200 mg twice daily for disease control but this was hindered by intolerable side effects including pruritus and skin exfoliation. In the meantime, she suffered a right hypertensive basal ganglia hemorrhage. Treatment was subsequently switched to cabergoline and the dose titrated to 0.5 mg daily. Fluconazole 400 mg daily was later added to control the persistent disease. Her clinical and biochemical parameters improved markedly three months after the addition of fluconazole. No adverse event was reported. Her disease has remained stable for the last 15 months up until the time of the recent clinic review. CONCLUSIONS: This case demonstrates the long-term efficacy of fluconazole in tandem with cabergoline for the control of recurrent Cushing's disease.
Journal of Neurological Surgery Part B Skull Base · 2017 · 0 citations
The Use of Mifepristone in the Perioperative Management of a Patient with Cushing's Disease
AbstractIntroduction: Mifepristone is a competitive antagonist of glucocorticoid receptors. Reversal of the clinical features of Cushing's disease/syndrome is most prominent at higher doses with overall clinical benefit of treatment occurring in close to 90% of patients who are refractory to other treatments. Serum cortisol may increase during treatment, which can lead to a confounding clinical picture in the setting of patients presenting for pituitary adenectomy.
Identification\nof the Clinical Candidate (<i>R</i>)‑(1-(4-Fluorophenyl)-6-((1-methyl‑1<i>H</i>‑pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro‑1<i>H</i>‑pyrazolo[3,4‑<i>g</i>]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone\n(CORT125134): A Selective Glucocorticoid Receptor (GR) Antagonist
AbstractThe nonselective\nglucocorticoid receptor (GR) antagonist mifepristone has been approved\nin the U.S. for the treatment of selected patients with Cushing’s\nsyndrome. While this drug is highly effective, lack of selectivity\nfor GR leads to unwanted side effects in some patients. Optimization\nof the previously described fused azadecalin series of selective GR\nantagonists led to the identification of CORT125134, which is currently\nbeing evaluated in a phase 2 clinical study in patients with Cushing’s\nsyndrome.
Disease module: DeepOracle (Open Targets). Approved indication: ChEMBL drug_indication (max_phase=4). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works, resolved on OpenAlex.
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