DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for split hand-foot malformation 3 — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleSplit hand-foot malformation 3 maps to a 2-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 split hand-foot malformation 3 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
beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC) — BTRC 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 2-fluorophenoxydrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6M90 · 2.05 Å · ligand 2-(2-fluorophenoxy)-3-{[2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carbonyl]amino}benzoic acid (J91). Experimental structure, not a prediction.
What the evidence adds up to
The 2008 study of a large consanguineous kindred with autosomal recessive split-hand/foot malformation identified a homozygous missense WNT10b mutation (p.R332W) in twelve affected members who had central feet reductions with or without hand involvement. One additional affected individual had a mild, atypical phenotype and did not carry the mutation. An asymptomatic female also carried the homozygous WNT10b mutation, suggesting either a second locus or a suppressor locus. The maximum multipoint lod score for the novel SHFM locus at 12q13.11-q13 was 5.47. Four of the five known SHFM loci were excluded, but in TP63 (SHFM4) most affected subjects carried a rare insertion variant (rs34201045) at the alternate promoter used for transcription of the N-terminal-truncated p63 isotype. This was the first reported WNT10b mutation in limb development and the first recessive mutation in SHFM.
The 2006 overview describes split hand/foot malformation as a developmental defect of the extremities resulting from errors in the initiation and maintenance of the apical ectodermal ridge. The phenotype is genetically heterogeneous and can be isolated or part of a malformation syndrome. The 2019 review of nonsyndromic SHFM notes that the condition is rare, highly complex, and characterised by clinical variability and irregular genetic inheritance. It provides an update of major molecular genetic alterations reported to date, intended to assist with molecular diagnosis, recurrence risk assessment, and management planning.
No drug or treatment is mentioned in any of these abstracts. No survival or response rates are given. The 2008 study reports a single family with twelve affected members and one non-penetrant carrier, so the findings cannot be generalised. The 2019 review does not present new experimental data.
What is still missing: a treatment for SHFM3, any clinical trial testing a drug, and a clear understanding of the genetic modifiers that cause variable expressivity and incomplete penetrance. Patient stratification by specific mutation and locus remains incomplete, and no funding for a therapeutic development programme has been described.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Human Molecular Genetics · 2008 · 81 citations
Homozygous WNT10b mutation and complex inheritance in Split-Hand/Foot Malformation
AbstractSplit-Hand/Foot Malformation (SHFM) is a complex limb malformation affecting the central rays of the autopod. We studied a large consanguineous kindred afflicted with autosomal recessive SHFM. Twelve affected members had central feet reductions with or without hand involvement while the remaining one had the mildest phenotype and atypical SHFM. We identified by homozygosity mapping a novel SHFM locus at 12q13.11-q13 with a maximum multipoint lod score of 5.47 and by subsequent candidate gene approach a homozygous missense WNT10b mutation (p.R332W) in all affected individuals but the atypical case plus in an asymptomatic female. We propose that either a second locus contributes to the manifestation of SHFM phenotype or a suppressor locus prevented trait manifestation in the non-penetrant female. We also investigated linkage to the five known SHFM loci. Four of the loci were excluded, while in TP63 [tumor protein p63 (SHFM4)], the only known gene responsible for SHFM, we detected in most affected subjects a rare insertion variant (rs34201045) at the alternate promoter used for transcription of the N-terminal-truncated p63 isotype. This is the first reported WNT10b mutation on the pathogenesis of limb development and recessive mutation in SHFM.
American Journal of Medical Genetics Part A · 2006 · 69 citations
The expanding panorama of split hand foot malformation
AbstractThe split hand/foot malformation is a developmental defect of the extremities resulting from errors in the initiation and maintenance of the apical ectodermal ridge. The phenotype is genetically heterogeneous, and it can be identified either as an isolated phenotypic manifestation or as a constituent component of a malformation syndrome. This overview describes the clinical phenotype, related animal models, and the evolving genetic heterogeneity of the malformation.
AbstractSplit-hand/foot malformation (SHFM) is a genetic limb anomaly disturbing the central rays of the autopod. SHFM is a genetically heterogeneous disorder with variable expressivity inherited as syndromic and nonsyndromic forms. We provide an update of the clinical and molecular aspects of nonsyndromic SHFM. This rare condition is highly complex due to the clinical variability and irregular genetic inheritance observed in the affected individuals. Nonsyndromic SHFM types have been reviewed in terms of major molecular genetic alterations reported to date. This updated overview will assist researchers, scientists, and clinicians in making an appropriate molecular diagnosis, providing an accurate recurrence risk assessment, and developing a management plan.
Is the Apert foot an overlooked aspect of this rare genetic disease? Clinical findings and treatment options for foot deformities in Apert syndrome
AbstractBACKGROUND: Apert syndrome is characterised by the presence of craniosynostosis, midface retrusion and syndactyly of hands and feet, thus, synonymously referred to as acrocephalosyndactyly type I. Considering these multidisciplinary issues, frequently requiring surgical interventions at an early age, deformities of the feet have often been neglected and seem to be underestimated in the management of Apert syndrome. Typical Apert foot features range from complete fusion of the toes and a central nail mass to syndactyly of the second to fifth toe with a medially deviated great toe; however, no clear treatment algorithms were presented so far. This article reviews the current existing literature regarding the treatment approach of foot deformities in Apert syndrome. STATE-OF-THE-ART TOPIC REVIEW: Overall, the main focus in the literature seems to be on the surgical approach to syndactyly separation of the toes and the management of the great toe deformity (hallux varus). Although the functional benefit of syndactyly separation in the foot has yet to be determined, some authors perform syndactyly separation usually in a staged procedure. Realignment of the great toe and first ray can be performed by multiple means including but not limited to second ray deletion, resection of the proximal phalanx delta bone on one side, corrective open wedge osteotomy, osteotomy of the osseous fusion between metatarsals I and II, and metatarsal I lengthening using gradual osteodistraction. Tarsal fusions and other anatomical variants may be present and have to be corrected on an individual basis. Shoe fitting problems are frequently mentioned as indication for surgery while insole support may be helpful to alleviate abnormal plantar pressures. CONCLUSION: There is a particular need for multicenter studies to better elaborate surgical indications and treatment plans for this rare entity. Plantar pressure measurements using pedobarography should be enforced in order to document the biomechanical foot development and abnormalities during growth, and to help with indication setting. Treatment options may include conservative means (i.e. insoles, orthopedic shoes) or surgery to improve biomechanics and normalize plantar pressures. LEVEL OF EVIDENCE: Level V.
Journal of Young Pharmacists · 2018 · 4 citations · open access
Sorafenib Induced Hand and Foot Syndrome
AbstractPublished on:January 2018 Journal of Young Pharmacists, 2018; 10(1):129-130 Case Report | doi:10.5530/jyp.2018.10.29 Authors: Dhanya Susan1, Malini M2, Remya Reghu* 1Pharm D intern, Department of Pharmacy Practice, Amrita School of Pharmacy, Kochi 682041, Amrita University, INDIA. 2Assistant Professor, Department of Pharmacy Practice, Amrita School of Pharmacy, Kochi 682041, Amrita University, INDIA. Abstract: Sorafenib a multikinase
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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