DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for WHIM syndrome 1 — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleWHIM syndrome 1 maps to a 1-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
approvedPlerixaforApproved drug
Structures already discussed alongside whim syndrome 1 in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
Structure of AMD3100-bound CXCR4/Gi complex — Plerixafor has a real, experimentally solved structure in complex with this target (PDB 8U4P, 3.15 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 vh6drag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8U4P · 3.15 Å · ligand Plerixafor (VH6). Experimental structure, not a prediction.
What the evidence adds up to
WHIM syndrome is a dominantly inherited primary immunodeficiency caused by mutations in the CXCR4 gene, leading to hyperfunction of the CXCR4 receptor and increased responsiveness to its ligand CXCL12. The acronym stands for Warts, Hypogammaglobulinaemia, Infections and Myelokathexis, the abnormal retention of mature neutrophils in the bone marrow. Patients suffer recurrent bacterial infections from childhood and have a specific susceptibility to HPV infections. Haematological findings include neutropenia, lymphopenia and hypogammaglobulinaemia. Because the disease is rare and its clinical presentation heterogeneous, diagnosis is often delayed, and in most patients the phenotype is incomplete at onset. Symptomatic treatments include G-CSF, substitutive immunoglobulins and antibiotic prophylaxis.
Plerixafor (Mozobil), a potent inhibitor of CXCR4 function, has been suggested as a treatment specifically targeting the molecular defect in WHIM syndrome. This suggestion is based on its efficacy as a CXCR4 antagonist, closing a translational research loop from the discovery that heterozygous mutations in CXCR4 cause the disease. To date, nine different mutations have been identified in humans, including eight truncation mutations and one missense mutation, E343K. The truncation mutations impair desensitisation by loss of phosphorylation sites in the C-terminus, enhancing G-protein activation and prolonging downstream signalling. The mechanism of the missense mutation E343K, which leaves all phosphorylation sites intact, has been characterised in HeLa cell lines: cells overexpressing CXCR4E343K, CXCR4E343R or CXCR4E343A showed enhanced cell migration, prolonged phosphorylation of ERK1/2, p38 and JNK1/2/3, aggravated activation of the PI3K/AKT/NF-κB pathway, and higher expression of TNFa and IL6. Only CXCR4 with a negatively charged residue at the 343 site maintained normal downstream signalling after activation with CXCL12.
One abstract reports a real-world experience with VMAT2 inhibitors (tetrabenazine, deutetrabenazine, valbenazine) for hyperkinetic movement disorders, not for WHIM syndrome. In that study of 135 patients, the most common diagnosis was Tourette syndrome/tics (49.6%). The VMAT2 inhibitors effectively controlled hyperkinetic movement disorders as measured by a 1-to-4-point Likert scale, with the proportion of patients scoring 1 (normal or mildly ill) rising from 13.0–26.7% before treatment to 60.9–71.9% while on treatment. Side effects were mild and improved after dose reduction, drug cessation or addition of adjunctive medications. The authors note that these drugs are not readily accessible in the United States for indications not approved by the FDA.
What remains missing is evidence from controlled clinical trials of plerixafor in WHIM syndrome patients, with clear endpoints for infection rates, wart burden, neutrophil counts and quality of life. The molecular work on the E343K mutation is limited to cell lines. No large, prospective, stratified study has been conducted, and the rarity of the disease makes recruitment and funding for such a trial difficult.
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 Molecular Medicine · 2011 · 88 citations
Clinical and Genetic Features of Warts, Hypogammaglobulinemia, Infections and Myelokathexis (WHIM) Syndrome
AbstractWHIM syndrome is a dominantly inherited primary immunodeficiency disorder representing the first identified example of human disease caused by mutations in the gene encoding for the chemokine receptor CXCR4. Pathogenesis is mediated by CXCR4 hyperfunction, leading to increased responsiveness to its unique ligand CXCL12 (also known as SDF-1). The altered CXCR4/CXCL12 interaction likely impairs cellular homeostasis and trafficking, resulting in immunological dysfunctions. The acronym WHIM resumes the main features of the syndrome: Warts, Hypogammaglobulinemia, Infections and Myelokathexis, which is abnormal retention of mature neutrophils in the bone marrow. WHIM patients suffer from recurrent bacterial infections since childhood and manifest a specific susceptibility to HPV infections. Hematological findings include neutropenia, lymphopenia and hypogammaglobulinemia. Because of the rarity of the disease and the heterogeneity in clinical presentation, diagnosis is often delayed. In the majority of patients, the phenotype is incomplete at the onset and WHIM syndrome is not suspected. Early identification may improve clinical and therapeutic management. Symptomatic treatments include G-CSF, substitutive immunoglobulins and antibiotic prophylaxis. A new therapeutic strategy might include the potent inhibitor of CXCR4 function plerixafor (Mozobil), as an agent specifically targeting the molecular defect in order to attenuate the phenotypic manifestations of the syndrome.
AbstractOBJECTIVES: The aim of this study was to review our "real-world" experience with the vesicular monoamine transporter 2 (VMAT2) inhibitors tetrabenazine (TBZ), deutetrabenazine (DTBZ), and valbenazine (VBZ) for treatment of hyperkinetic movement disorders. Access and adherence to VMAT2 inhibitors may be limited by insurance and regulatory issues, inexperience with their use by the prescribing physician, lack of efficacy, or side effects. METHODS: We performed a retrospective chart review, supplemented with a questionnaire, of all our patients treated with a VMAT2 inhibitor between January 1, 2017, and August 30, 2018. RESULTS: We identified 135 patients (57.8% male) and 178 prescriptions for VMAT2 inhibitors (TBZ, n = 45 [25.3%]; DTBZ, n = 104 [58.4%]; VBZ, n = 29 [16.3%]). Tourette syndrome/tics was the most common diagnosis (n = 67 [49.6%]) for which VMAT2 inhibitors were prescribed. The VMAT2 inhibitor mean treatment durations (range; SD) and daily dosages (range; SD) were as follows: TBZ (n = 31), 5.1 months (1-19; 3.9) at 48.8 mg (12.5-112.5; 29.6); DTBZ (n = 51), 8.0 months (0.25-16.5; 4.4) at 34.4 mg (6-96; 20.7); and VBZ (n = 20), 6.0 months (0.1-16; 5.6) at 64 mg (40-160; 35.3). The VMAT2 inhibitors effectively controlled hyperkinetic movement disorders as measured by a 1- to 4-point Likert scale (1 = normal or mildly ill, 4 = severely ill) comparing illness severity before starting and while on treatment (score of 1 in 13.0%-26.7% vs 60.9%-71.9% of patients). Side effects were mild and improved or resolved following dose reduction, drug cessation, or addition of adjunctive medications. CONCLUSIONS: The VMAT2 inhibitors are effective and safe in a range of hyperkinetic movement disorders but are not readily accessible by patients in the United States for indications not approved by the Food and Drug Administration.
British Journal of Haematology · 2013 · 48 citations · open access
Genetics on a <scp>WHIM</scp>
AbstractWe initially described the WHIM syndrome based on the combination of Warts, Hypogammaglobulinaemia, Infections and Myelokathexis (neutrophil retention in the bone marrow). Translational research led to the discovery that this rare immunodeficiency disease is caused by a heterozygous mutation in the CXCR4 gene. Recently, Plerixafor has been suggested as a treatment for WHIM syndrome due to its efficacy as a CXCR4 antagonist, closing the translational research loop. In this review, we will focus on the clinical manifestations, pathophysiology, diagnosis and possible therapies for this rare entity.
The negative charge of the 343 site is essential for maintaining physiological functions of CXCR4
AbstractAbstract Background Warts, hypogammaglobulinemia, recurrent bacterial infections and myelokathexis (WHIM) syndrome is a primary immunodeficiency disease (PID) usually caused by autosomal dominant mutations in the chemokine receptor CXCR4 gene. To date, a total of nine different mutations including eight truncation mutations and one missense mutation (E343K, CXCR4E343K) distributed in the C-terminus of CXCR4 have been identified in humans. Studies have clarified that the loss of phosphorylation sites in the C-terminus of truncated CXCR4 impairs the desensitization process, enhances the activation of G-protein, prolongs downstream signaling pathways and introduces over immune responses, thereby causing WHIM syndrome. So far, there is only one reported case of WHIM syndrome with a missense mutation, CXCR4E343K, which has a full length of C-terminus with entire phosphorylation sites, no change in all potential phosphorylation sites. The mechanism of the missense mutation (CXCR4E343K) causing WHIM syndrome is unknown. This study aimed to characterize the effect of mutation at the 343 site of CXCR4 causing the replacement of arginine/E with glutamic acid/K on the receptor signal transduction, and elucidate the mechanism underling CXCR4E343K causing WHIM in the reported family. Results We completed a series of mutagenesis to generate different mutations at the 343 site of CXCR4 tail, and established a series of HeLa cell lines stably expressing CXCR4WT or CXCR4E343D (glutamic acid/E replaced with aspartic acid/D) or CXCR4E343K (glutamic acid/E replaced with lysine/K) or CXCR4E343R (glutamic acid/E replaced with arginine/R) or CXCR4E343A (glutamic acid/E replaced with alanine/A) and then systematically analyzed functions of the CXCR4 mutants above. Results showed that the cells overexpressing of CXCR4E343D had no functional changes with comparison that of wild type CXCR4. However, the cells overexpressing of CXCR4E343K or CXCR4E343R or CXCR4E343A had enhanced cell migration, prolonged the phosphorylation of ERK1/2, p38, JNK1/2/3, aggravated activation of PI3K/AKT/NF-κB signal pathway, introduced higher expression of TNFa and IL6, suggesting over immune response occurred in CXCR4 mutants with charge change at the 343 site of receptor tail, as a result, causing WHIM syndrome. Biochemical analysis of those mutations at the 343 site of CXCR4 above shows that CXCR4 mutants with no matter positive or neutral charge have aberrant signal pathways downstream of activated mutated CXCR4, only CXVR4 with negative charge residues at the site shows normal signal pathway post activation with stromal-derived factor (SDF1, also known as CXCL12). Conclusion Taken together, our results demonstrated that the negative charge at the 343 site of CXCR4 plays an essential role in regulating the down-stream signal transduction of CXCR4 for physiological events, and residue charge changes, no matter positive or neutral introduce aberrant activities and functions of CXCR4, thus consequently lead to WHIM syndrome.
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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