DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for pituitary-dependent Cushing's disease — screening already-approved drugs against its 13-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease modulePituitary-dependent Cushing's disease maps to a 13-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
approvedPasireotideApproved drugapprovedKetoconazoleApproved drug
Structures already discussed alongside pituitary-dependent cushing's disease in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
Crystal structure of CYP105A1 R84A and ketoconazole complex — Ketoconazole has a real, experimentally solved structure in complex with this target (PDB 9KW2, 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 ktndrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9KW2 · 1.8 Å · ligand Ketoconazole (KTN). Experimental structure, not a prediction.
What the evidence adds up to
First-line pituitary surgery produces remission in about 78% of patients, with relapse in about 13% over ten years, so that roughly one third of patients eventually require second-line treatment. In a Bulgarian cohort of 242 surgical patients, the initial remission rate was 74%, of whom 10% later relapsed; over long-term follow-up 36% had active disease (26% persistent, 10% relapsed). Repeat pituitary surgery cures about 50% of cases. Bilateral adrenalectomy resolves hypercortisolaemia in nearly all patients but leaves permanent glucocorticoid and mineralocorticoid deficiency, and Nelson’s syndrome occurs in up to 35% of adrenalectomised patients. Pituitary radiotherapy controls cortisol excess in a large percentage of patients but takes years to reach full effect and carries a considerable risk of hypopituitarism.
Medical therapy is now used pre-surgically for severe disease, post-surgically after failed or incomplete resection, as bridging during radiotherapy, or as primary therapy when surgery is not an option. In the Bulgarian cohort, remission rates for single drugs were: dopamine agonists 20%, pasireotide 30%, and ketoconazole 63%. Ketoconazole is the most commonly used adrenal-directed drug because of its rapid action. The glucocorticoid receptor antagonist mifepristone is effective for glucose intolerance and is approved for Cushing’s syndrome with impaired glucose metabolism when surgery is not indicated. Pasireotide is approved for Cushing’s disease when surgery has failed or is not an option. Combining drugs with different mechanisms of action improved results in the Bulgarian series. However, pharmacologic treatment is often associated with side effects that are a powerful deterrent to its use.
A 2022 systematic review focused on MRI-negative Cushing’s disease but did not provide new efficacy data. A 2025 update described diagnostic and treatment advances but offered no new numerical outcomes. The 2018 Bulgarian study, the largest single-centre cohort reported, concluded that a significant percentage of patients with persistent or recurrent Cushing’s disease require a polymodal approach and a multidisciplinary team to achieve long-term remission.
What remains missing are prospective trials that directly compare drug combinations head-to-head, long-term data on quality of life and mortality for each second-line strategy, and reliable biomarkers to predict which patients will respond to pituitary-directed drugs versus adrenal-directed drugs. The evidence base still lacks the funding and trial designs needed to stratify patients by tumour size, MRI status, or genetic profile before choosing a second-line treatment.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
New England Journal of Medicine · 2012 · 641 citations · open access
A 12-Month Phase 3 Study of Pasireotide in Cushing's Disease
AbstractBACKGROUND: Cushing's disease is associated with high morbidity and mortality. Pasireotide, a potential therapy, has a unique, broad somatostatin-receptor-binding profile, with high binding affinity for somatostatin-receptor subtype 5. METHODS: In this double-blind, phase 3 study, we randomly assigned 162 adults with Cushing's disease and a urinary free cortisol level of at least 1.5 times the upper limit of the normal range to receive subcutaneous pasireotide at a dose of 600 μg (82 patients) or 900 μg (80 patients) twice daily. Patients with urinary free cortisol not exceeding 2 times the upper limit of the normal range and not exceeding the baseline level at month 3 continued to receive their randomly assigned dose; all others received an additional 300 μg twice daily. The primary end point was a urinary free cortisol level at or below the upper limit of the normal range at month 6 without an increased dose. Open-label treatment continued through month 12. RESULTS: Twelve of the 82 patients in the 600-μg group and 21 of the 80 patients in the 900-μg group met the primary end point. The median urinary free cortisol level decreased by approximately 50% by month 2 and remained stable in both groups. A normal urinary free cortisol level was achieved more frequently in patients with baseline levels not exceeding 5 times the upper limit of the normal range than in patients with higher baseline levels. Serum and salivary cortisol and plasma corticotropin levels decreased, and clinical signs and symptoms of Cushing's disease diminished. Pasireotide was associated with hyperglycemia-related adverse events in 118 of 162 patients; other adverse events were similar to those associated with other somatostatin analogues. Despite declines in cortisol levels, blood glucose and glycated hemoglobin levels increased soon after treatment initiation and then stabilized; treatment with a glucose-lowering medication was initiated in 74 of 162 patients. CONCLUSIONS: The significant decrease in cortisol levels in patients with Cushing's disease who received pasireotide supports its potential use as a targeted treatment for corticotropin-secreting pituitary adenomas. (Funded by Novartis Pharma; ClinicalTrials.gov number, NCT00434148.).
Endocrine Reviews · 2015 · 465 citations · open access
The Treatment of Cushing's Disease
AbstractCushing's disease (CD), or pituitary-dependent Cushing's syndrome, is a severe endocrine disease caused by a corticotroph pituitary tumor and associated with increased morbidity and mortality. The first-line treatment for CD is pituitary surgery, which is followed by disease remission in around 78% and relapse in around 13% of patients during the 10-year period after surgery, so that nearly one third of patients experience in the long-term a failure of surgery and require an additional second-line treatment. Patients with persistent or recurrent CD require additional treatments, including pituitary radiotherapy, adrenal surgery, and/or medical therapy. Pituitary radiotherapy is effective in controlling cortisol excess in a large percentage of patients, but it is associated with a considerable risk of hypopituitarism. Adrenal surgery is followed by a rapid and definitive control of cortisol excess in nearly all patients, but it induces adrenal insufficiency. Medical therapy has recently acquired a more important role compared to the past, due to the recent employment of novel compounds able to control cortisol secretion or action. Currently, medical therapy is used as a presurgical treatment, particularly for severe disease; or as postsurgical treatment, in cases of failure or incomplete surgical tumor resection; or as bridging therapy before, during, and after radiotherapy while waiting for disease control; or, in selected cases, as primary therapy, mainly when surgery is not an option. The adrenal-directed drug ketoconazole is the most commonly used drug, mainly because of its rapid action, whereas the glucocorticoid receptor antagonist, mifepristone, is highly effective in controlling clinical comorbidities, mainly glucose intolerance, thus being a useful treatment for CD when it is associated with diabetes mellitus. Pituitary-directed drugs have the advantage of acting at the site responsible for CD, the pituitary tumor. Among this group of drugs, the dopamine agonist cabergoline and the somatostatin analog pasireotide result in disease remission in a consistent subgroup of patients with CD. Recently, pasireotide has been approved for the treatment of CD when surgery has failed or when surgery is not an option, and mifepristone has been approved for the treatment of Cushing's syndrome when associated with impairment of glucose metabolism in case of the lack of a surgical indication. Recent experience suggests that the combination of different drugs may be able to control cortisol excess in a great majority of patients with CD.
Current Opinion in Endocrinology Diabetes and Obesity · 2007 · 24 citations
Second-line treatment for Cushing's disease when initial pituitary surgery is unsuccessful
AbstractPURPOSE OF REVIEW: Adenectomy via transsphenoidal surgery is considered the treatment of choice for Cushing's disease. It is successful in about 80% of patients in the hands of an experienced surgeon. When transsphenoidal surgery fails or is contraindicated, a second-line treatment must be chosen. The review focuses on second-line treatment options. RECENT FINDINGS: Repeat pituitary surgery results in the cure of Cushing's disease in about 50% of cases. Bilateral adrenalectomy results in resolution of hypercortisolemia in almost all patients, but leaves the patient glucocorticoid and mineralocorticoid deficient. Nelson's syndrome, depending on the definition, occurs in up to 35% of these patients. Irradiation of the residual pituitary tumor typically takes several years before the full effect is realized; it can cause panhypopituitarism. Finally, pharmacologic treatment of persistent hypercortisolemia can be effective, but is often associated with untoward side effects. These side effects are a powerful deterrent to its use. Several new pharmacologic agents are being studied and show some promise. SUMMARY: Each of the second-line treatments for Cushing's disease currently available can be effective at treating hypercortisolism, but each has significant limitations. New pharmacologic agents may soon offer some very exciting treatment options.
Expert Opinion on Investigational Drugs · 2010 · 21 citations
Pasireotide for the treatment of Cushing's disease
AbstractIMPORTANCE OF THE FIELD: It is important to treat patients with Cushing's disease as rapidly as possible to limit both the mortality and morbidity of the disease. Pituitary surgery remains the treatment of choice, but the rate of cure at long-term follow-up is suboptimal and recurrence rates are high. If surgery fails or relapse occurs, no treatment has proven to be fully satisfactory. Currently available medical therapies are considered a transient and palliative treatment. However, recently there has been renewed interest in medical therapy due to new insights in pathogenetic mechanisms of corticotroph pituitary tumors. AREAS COVERED IN THIS REVIEW: We summarize the pharmacodynamics and possible mechanism of action of pasireotide (SOM230), a novel multireceptor-targeted somatostatin analogue. Pasireotide has a unique binding profile, with high affinity for four of the five somatostatin receptors, especially SSTR(5), the receptor most prevalent in corticotroph tumors. WHAT THE READER WILL GAIN: The reader should gain an understanding of preclinical and clinical data supporting the potential use of pasireotide in patients with Cushing's disease. TAKE HOME MESSAGE: Preliminary data suggest that pasireotide shows promise as a tumor-targeted medical therapy in patients with Cushing's disease. If the efficacy of pasireotide is confirmed by larger studies, this compound may be a useful treatment option not only in patients with severe Cushing's disease, but also in patients with mild hypercortisolism where its efficacy might be more evident.
Journal of Endocrinological Investigation · 2016 · 12 citations · open access
Role of “old” pharmacological agents in the treatment of Cushing’s syndrome
AbstractDespite recent advances in the management of endogenous Cushing's syndrome (CS), its treatment remains a challenge. When surgery has been unsuccessful or unfeasible as well in case of recurrence, the "old" pharmacological agents represent an important alternative for both ACTH-dependent and independent hypercortisolism. Especially in the latter, the advent of novel molecules directly targeting ACTH secretion has not outweighed the "old" drugs, which continue to be largely employed and have recently undergone a reappraisal. This review provides a survey of the "old" pharmacological agents in the treatment of CS.
Hormone and Metabolic Research · 2018 · 6 citations
Cushing’s Syndrome: A Historic Review of the Treatment Strategies and Corresponding Outcomes in a Single Tertiary Center over the Past Half-Century
AbstractCushing's syndrome (CS) is associated with serious comorbidities and an increased mortality rate that could be reduced only if strict biochemical control is achieved. The aim of this study was to show the 50-year experience of a single tertiary center in the management of CS patients - the different treatment modalities used over the years and the corresponding outcomes. It was a retrospective study of a large cohort of patients from the Bulgarian CS database: 613 patients (374 with ACTH-dependent and 239 with ACTH-independent CS). Pituitary surgery was applied to 242 patients with Cushing's disease (CD) with initial remission rate of 74% of which 10% relapsed. Approximately 36% manifested with active disease during the long-term follow-up (26% with persistent disease, 10% relapses) most of which were subjected to a secondary treatment (13.6% to pituitary resurgery, 14% to pituitary radiotherapy, and 5.4% to bilateral adrenalectomy). A total of 294 CD patients received medical therapy with overall remission rates for the most commonly used drugs: dopamine agonists 20%, pasireotide 30%, and ketoconazole 63%. Significant improvement of results was achieved by combining drugs with different mechanisms of action. Regardless of the progress in the neurosurgery and radiotherapy techniques and new drugs discovery, the management of patients with CS remains a real challenge for physicians. Not only patients with adrenal carcinoma but also significant percentage of subjects with persistent and recurrent Cushing's disease often require a polymodal approach and the efforts of a multidisciplinary highly qualified, experienced, and motivated team in order to achieve a long-term remission.
Journal of Neurological Surgery Part B Skull Base · 2022 · 1 citations
MRI-Negative Cushing's Disease: A Systematic Review and Meta-Analysis
AbstractObjective: In this systematic review and meta-analysis, we review the literature regarding pituitary-dependent Cushing's disease (CD) patients with negative or inconclusive MRI. This review will analyze demographics, information about the type of operation, and surgical outcomes such as remission, persistence, and recurrence. Based on this information, we will suggest which therapeutic approach is more efficient in managing patients with pituitary-dependent CD.
Journal of Pharmaceutical Sciences & Emerging Drugs · 2013 · 1 citations · open access
Pituitary-Directed Drug Therapy for the Treatment of Cushing's Disease
AbstractPituitary-Directed Drug Therapy for the Treatment of Cushing’s Disease Cushing’s disease (CD) is usually the result of an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma. The result is overstimulation of the adrenal glands leading to chronic hypercortisolism. Individuals with CD have increased risks of hypertension, obesity, hyperglycemia, infections, and vascular damage. Transsphenoidal surgery of the pituitary adenoma is the preferred option in the treatment of CD. The success rates are 65- 90% for microadenomas; however, as many as 40% of patients will experience recurrence within 10 years.
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.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
