DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Noonan syndrome 5 — screening already-approved drugs against its 3-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleNoonan syndrome 5 maps to a 3-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 noonan syndrome 5 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
Raf-1 proto-oncogene, serine/threonine kinase (RAF1) — RAF1 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 agsdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9MMQ · 2.9 Å · ligand PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER (AGS). Experimental structure, not a prediction.
What the evidence adds up to
In a cohort of 50 Brazilian probands with Noonan syndrome who had no pathogenic variants in the 11 known genes, whole-exome sequencing identified rare missense variants in SOS2 in 4% and in LZTR1 in 8%. These variants segregated in one American and one Polish family as well. The authors estimate that mutations in these two genes account for approximately 3% of all Noonan syndrome cases. SOS2 variants were seen in patients with marked ectodermal involvement, similar to patients with SOS1 mutations. The functional role of LZTR1 in the RAS/MAPK pathway remains unknown.
An 18-month-old girl with Noonan syndrome, pulmonary stenosis, and hypertrophic cardiomyopathy developed spontaneous chylothorax that did not respond to thoracic duct ligation, tetracycline pleurodesis, or pleurectomy over two months. A low-fat diet helped but did not resolve the effusion. Oral prednisone at 1 mg/kg twice daily, slowly tapered over three months, led to resolution with no recurrence during eight months of follow-up. The authors note that a controlled clinical trial would be difficult in such a rare complication.
Noonan syndrome is an autosomal dominant disorder caused by dysregulation of the RAS/MAPK pathway. Prevalence estimates range from 1 in 1000 to 1 in 2500 live births, or 1–2 per 20,000 newborns depending on the source. Missense mutations in PTPN11 account for approximately 50% of cases. Other genes include SOS1, RAF1, KRAS, BRAF, NRAS, MAP2K1, RIT1, SOS2, LZTR1, and A2ML1. A novel RIT1 mutation has been reported to worsen cardiac hypertrophy in Noonan syndrome.
What is still missing is a controlled trial of prednisone for chylothorax in Noonan syndrome, which would require multicentre collaboration given the rarity of the complication. Functional studies to clarify the role of LZTR1 in RAS/MAPK signalling are lacking. No drug has been tested in a randomised trial for any core feature of Noonan syndrome itself.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Journal of Medical Genetics · 2015 · 245 citations · open access
Rare variants in <i>SOS2</i> and <i>LZTR1</i> are associated with Noonan syndrome
AbstractBACKGROUND: Noonan syndrome is an autosomal dominant, multisystemic disorder caused by dysregulation of the RAS/mitogen activated protein kinase (MAPK) pathway. Heterozygous, pathogenic variants in 11 known genes account for approximately 80% of cases. The identification of novel genes associated with Noonan syndrome has become increasingly challenging, since they might be responsible for very small fractions of the cases. METHODS: A cohort of 50 Brazilian probands negative for pathogenic variants in the known genes associated with Noonan syndrome was tested through whole-exome sequencing along with the relatives in the familial cases. Families from the USA and Poland with mutations in the newly identified genes were included subsequently. RESULTS: We identified rare, segregating or de novo missense variants in SOS2 and LZTR1 in 4% and 8%, respectively, of the 50 Brazilian probands. SOS2 and LZTR1 variants were also found to segregate in one American and one Polish family. Notably, SOS2 variants were identified in patients with marked ectodermal involvement, similar to patients with SOS1 mutations. CONCLUSIONS: We identified two novel genes, SOS2 and LZTR1, associated with Noonan syndrome, thereby expanding the molecular spectrum of RASopathies. Mutations in these genes are responsible for approximately 3% of all patients with Noonan syndrome. While SOS2 is a natural candidate, because of its homology with SOS1, the functional role of LZTR1 in the RAS/MAPK pathway is not known, and it could not have been identified without the large pedigrees. Additional functional studies are needed to elucidate the role of LZTR1 in RAS/MAPK signalling and in the pathogenesis of Noonan syndrome.
American journal of diseases of children · 1992 · 37 citations
Spontaneous Chylothorax in Noonan Syndrome
AbstractOBJECTIVE: To describe a case of spontaneous chylothorax in a child with Noonan syndrome successfully treated with prednisone. DESIGN: Case report. SETTING: A pediatric cardiology referral center for the Rocky Mountain region. PATIENT: An 18-month-old girl with Noonan's syndrome, pulmonary stenosis, and hypertrophic cardiomyopathy who presented with spontaneous chylothorax. INTERVENTIONS: The child's chylothorax did not respond to thoracic duct ligation, tetracycline pleurodesis, and pleurectomy during a 2-month period. A low-fat diet was helpful but did not eliminate the problem. Prednisone was started orally at 1 mg/kg per dose twice daily and slowly tapered during 3 months. The chylothorax did not recur during 8 months of follow-up. CONCLUSIONS: Prednisone may be useful in the treatment of chylothorax in Noonan syndrome. A controlled clinical trial would be helpful but would be difficult in such a rare complication of an uncommon syndrome.
Clinical and Genetic Characteristics of Noonan Syndrome and Noonan-like Diseases
AbstractNoonan syndrome (NS) is a group of inherited autosomal dominant diseases characterized by a disturbance of the RAS-MAPK signaling pathway and leading to various clinical manifestations. The prevalence in the world is estimated at 1–2 per 20 000 newborns. The review discusses the molecular genetic causes of the disease, the characteristics of the clinical manifestations of the disease, and the methods of molecular genetic diagnosis.
A novel RIT1 mutation causes deterioration of Noonan syndrome-associated cardiac hypertrophy
AbstractNoonan syndrome (NS) is an autosomal dominant inherited condition characterized by unusual facial features, short stature, congenital heart disease, bleeding problems, metabolic and endocrine abnormalities, and other problems [1]. An estimated 1 in 1000–2500 live births are affected by various forms of the disease [2]. Multiple genotype-phenotype analyses have revealed numerous gene mutations (PTPN11, SOS1, RAF1, KRAS, BRAF, NRAS, MAP2K1, RIT1, SOS2, LZTR1, and A2ML1) that result in NS, typically involving hyperactivation of the RAS-MAPK pathway and leading to various developmental disorders.
Encyclopedia of Life Sciences · 2006 · 2 citations
Noonan Syndrome
AbstractAbstract Noonan syndrome is a genetic disorder inherited as an autosomal trait or occurring sporadically, characterized by short stature, dysmorphic facies, webbed neck, congenital heart disease or hypertrophic cardiomyopathy, skeletal anomalies, cryptorchidism and developmental delay. Missense mutations in the PTPN11 gene, encoding the protein tyrosine phosphatase SHP‐2, cause approximately 50% of cases.
Journal of Evolution of Medical and Dental Sciences · 2015 · 0 citations · open access
NOONAN SYNDROME: AN EARLY DIAGNOSIS
AbstractNoonan syndrome is a genetic multisystem disorder characterised by facial dysmorphism, learning difficulties, developmental delay, short stature, cardiac defects, bleeding manifestations and lymphatic malformation affecting 1 in 1000-2500 children. This is a case report of a twenty six month old boy diagnosed to have Noonan syndrome with sporadic inheritance secondary to advanced paternal age. Multidisciplinary approach is the key to success in managing these children, who are diagnosed at an early age.
AbstractNoonan syndrome is an autosomal dominant, genetic, multisystem disorder with a prevalence of 1 in 1000-2500 live births. Characteristic features of the condition include distinctive myopathic facial features, hypertelorism, short and broad nose, webbed neck, and low set ears. About 10% of the subjects have auditory defects due to sensorineural hearing loss. The patient also has short stature, chest deformity (superior pectus carinatum and inferior pectus excavatum), widely spaced nipples, and delayed puberty. A rare psychiatric manifestation of somnambulism and somniloquy in a case of Noonan syndrome is reported.
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.
