DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for systemic mastocytosis — screening already-approved drugs against its 27-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleSystemic mastocytosis maps to a 27-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
approvedSunitinibApproved drug
Structures already discussed alongside systemic mastocytosis in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
KIT kinase domain — Sunitinib has a real, experimentally solved structure in complex with this target (PDB 3G0E, 1.6 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 b49drag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3G0E · 1.6 Å · ligand Sunitinib (B49). Experimental structure, not a prediction.
What the evidence adds up to
In a retrospective review of 342 adult patients at the Mayo Clinic, life expectancy in indolent systemic mastocytosis was not significantly different from that of the control population, but prognosis was worse in the smouldering variant. Cladribine and interferon alpha were the most effective drugs. Experience with imatinib mesylate or other anti-KIT D816V kinase inhibitors showed limited treatment success. TET2 mutations were found in about 29% of patients, but their relevance to pathogenesis or treatment was unknown.
A phase 3 randomised placebo-controlled trial of masitinib enrolled 135 patients with severely symptomatic indolent or smouldering systemic mastocytosis who had not responded to optimal symptomatic treatments. By 24 weeks, masitinib produced a cumulative response of 18.7% (122.6 responses out of 656.5 possible responses) compared with 7.4% for placebo (48.9 of 656.5), a difference of 11.3% (odds ratio 3.6, 95% CI 1.2–10.8, p=0.0076). Frequent severe adverse events with masitinib included diarrhoea (11% vs 2% on placebo), rash (6% vs none), and asthenia (6% vs 2%). No life-threatening toxicities occurred; one placebo patient died from an unrelated cause.
A case report described the first use of sunitinib, a multi-targeted tyrosine kinase inhibitor, in a patient with systemic mastocytosis. The authors noted that some TKIs had been used successfully in uncommon cases of systemic mastocytosis that do not carry the usual imatinib-resistant KIT D816V mutation. No controlled data from this report are available.
What remains missing is prospective evidence that any drug improves overall survival in advanced systemic mastocytosis, randomised data for cladribine or interferon alpha, and any validated biomarker to predict which patients will respond to masitinib or other kinase inhibitors. The masitinib trial’s primary endpoint was a composite of symptom scores, not a hard outcome such as progression or death, and the response rate on drug was still below 20%. No trial has yet stratified patients by KIT mutation status or TET2 mutation status to guide treatment selection.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Current Opinion in Hematology · 2010 · 98 citations
Systemic mastocytosis in adults: a review on prognosis and treatment based on 342 Mayo Clinic patients and current literature
AbstractPURPOSE OF REVIEW: Systemic mastocytosis is a neoplastic disease of mast cells that often harbors a KIT mutation and involves the bone marrow. The current review provides an update on prognosis and treatment of systemic mastocytosis, including investigational drug therapy. RECENT FINDINGS: We have recently examined survival data and treatment outcome in 342 adult patients with systemic mastocytosis seen at our institution. Life expectancy in indolent systemic mastocytosis was not significantly different than that of the control population; however, prognosis was not as good in the WHO indolent systemic mastocytosis variant of smoldering mastocytosis. Prognosis in systemic mastocytosis associated with another myeloid malignancy was significantly better in the absence of morphological features of myelodysplasia or monocytosis. On the contrary, although prevalent, eosinophilia had little prognostic impact. Cladribine and interferon alpha were therapeutically the most effective drugs. Current experience suggests limited treatment success with either imatinib mesylate or other anti-KIT D816V kinase inhibitors. TET2 mutations have recently been described in approximately 29% of patients with systemic mastocytosis, but their pathogenetic or treatment relevance is unknown. SUMMARY: Primary data from a large series of patients have enabled delineation of well defined prognostic groups in systemic mastocytosis and clarification of the merits of conventional drugs for aggressive systemic mastocytosis.
Case Report: Treatment of systemic mastocytosis with sunitinib
Abstract<ns4:p> Mast cell activation disease typically presents as chronic multisystem polymorbidity of generally inflammatory ± allergic theme. Presently, treatment of the rare, cytoproliferative variant systemic mastocytosis employs empirically selected therapies to impede mast cell mediator production and action and, when necessary, inhibition of proliferation. Some tyrosine kinase inhibitors (TKIs) have been used successfully in uncommon cases of systemic mastocytosis not bearing that disease’s usual imatinib-resistant KIT <ns4:sup>D816V</ns4:sup> mutation. Recently, sunitinib, a multi-targeted TKI, had been successful in a case of systemic mast cell activation syndrome. In addition, most allergy is principally a mast cell activation phenomenon, and sunitinib has been shown helpful in controlling a murine model of oral allergy syndrome. Here, we present the first use of sunitinib in systemic mastocytosis. </ns4:p>
Open Science Framework · 2017 · 0 citations · open access
Masitinib for treatment of severely symptomatic indolent systemic mastocytosis: a randomised, placebo-controlled, phase 3 study
AbstractBackground:Indolent systemic mastocytosis, including the subvariant of smouldering systemic mastocytosis, is a lifelong condition associated with reduced quality of life. Masitinib inhibits KIT and LYN kinases that are involved in indolent systemic mastocytosis pathogenesis. We aimed to assess safety and efficacy of masitinib versus placebo in severely symptomatic patients who were unresponsive to optimal symptomatic treatments.Methods:In this randomised, double-blind, placebo-controlled, phase 3 study, we enrolled adults (aged 18–75 years) with indolent or smouldering systemic mastocytosis, according to WHO classification or documented mastocytosis based on histological criteria, at 50 centres in 15 countries. We excluded patients with cutaneous or non-severe systemic mastocytosis after a protocol amendment. Patients were centrally randomised (1:1) to receive either oral masitinib (6 mg/kg per day over 24 weeks with possible extension) or matched placebo with minimisation according to severe symptoms. The primary endpoint was cumulative response (≥75% improvement from baseline within weeks 8–24) in at least one severe baseline symptom from the following: pruritus score of 9 or more, eight or more flushes per week, Hamilton Rating Scale for Depression of 19 or more, or Fatigue Impact Scale of 75 or more. We assessed treatment effect using repeated measures methodology for rare diseases via the generalised estimating equation model in a modified intention-to-treat population, including all participants assigned to treatment minus those who withdrew due to a non-treatment-related cause. We assessed safety in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00814073. Findings: Between Feb 19, 2009, and July 15, 2015, 135 patients were randomly assigned to masitinib (n=71) or placebo (n=64). By 24 weeks, masitinib was associated with a cumulative response of 18·7% in the primary endpoint (122·6 responses of 656·5 possible responses [weighted generalised estimating equation]) compared with 7·4% for placebo (48·9 of 656·5; difference 11·3%; odds ratio 3·6; 95% CI 1·2–10·8; p=0·0076). Frequent severe adverse events (>4% difference from placebo) were diarrhoea (eight [11%] of 70 in the masitinib group vs one [2%] of 63 in the placebo group), rash (four [6%] vs none), and asthenia (four [6%] vs one [2%]). The most frequent serious adverse events were diarrhoea (three patients [4%] vs one [2%]) and urticaria (two [3%] vs none), and no life-threatening toxicities occurred. One patient in the placebo group died (unrelated to study treatment). Interpretation:These study findings indicate that masitinib is an effective and well tolerated agent for the treatment of severely symptomatic indolent or smouldering systemic mastocytosis. Funding: AB Science (Paris, France)
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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