Navigation through high-dimensional chemical space: discovery of Ba5Y13[SiO4]8O8.5 and Ba3Y2[Si2O7]2.

Two compounds were discovered in the well-studied BaO-Y2O3-SiO2 phase field. Two different experimental routines were used for the exploration of this system due to the differences of synthetic conditions and competition with a glass field. The first phase Ba5Y13[SiO4]8O8.5 was isolated through a combination of energy dispersive X-ray spectroscopy analysis and diffraction techniques which guided the exploration. The second phase Ba3Y2[Si2O7]2 was located using iterative algorithmic identification of target compositions. The structure solution of the new compounds was aided by continuous rotation electron diffraction, and the structures were refined against combined synchrotron and neutron time-of-flight powder diffraction. Ba5Y13[SiO4]8O8.5 crystallizes in I4̄2m, a = 18.92732(1), c = 5.357307(6) Å and represents its own structure type which combines elements of structures of known silicates embedded in columns of interconnected yttrium-centred polyhedra characteristic of high-pressure phases. Ba3Y2[Si2O7]2 has P21 symmetry with a pseudo-tetragonal cell (a = 16.47640(4), b = 9.04150(5), c = 9.04114(7) Å, ß = 90.0122(9)°) and is a direct superstructure of the Ca3BaBi[P2O7]2 structure. Despite the lower symmetry, the structure of Ba3Y2[Si2O7]2 retains disorder in both Ba/Y sites and disilicate network, thus presenting a superposition of possible locally-ordered fragments. Ba5Y13[SiO4]8O8.5 has low thermal conductivity of 1.04(5) W m-1 K-1 at room temperature. The two discovered phases provide a rich structural platform for further functional material design. The interplay of automated unknown phase composition identification with multiple diffraction methods offers acceleration of the time-consuming exploration of high-dimensional chemical spaces for new structures.

Clinical and methylomic features of spinal meningiomas.

PURPOSE: The objective of our study was to analyze methylomic and clinical features of a cohort of spinal meningiomas (SMs) resected at our institution. METHODS: This is a retrospective study of patients undergoing SM resection at our institution between 2010 and 2023. Clinical and radiographic characteristics were reviewed and analyzed with standard statistical methods. A Partitioning Around Medoids approach was used to cluster SMs with methylation data in a combined cohort from our institution and a publicly available dataset by methylation profiles. Clinical variables and pathway analyses were compared for the resulting clusters. RESULTS: Sixty-five SMs were resected in 53 patients with median radiographic follow-up of 34 months. Forty-six (87%) patients were female. The median age at surgery was 65 years and median tumor diameter was 1.9 cm. The five-year progression-free survival rate was 90%, with subtotal resection being associated with recurrence or progression (p = .017). SMs clustered into hypermethylation, intermediate methylation, and hypomethylation subgroups. Tumors in the hypermethylated subgroup were associated with higher WHO grade (p = .046) and higher risk histological subtypes (p <.001), while tumors in the hypomethylated subgroup were least likely to present with copy-number loss in chromosome 22q (p <.0001). SMs classified as immune-enriched under a previously developed intracranial meningioma classifier did not have increased leukocyte fractions or hypomethylation of genes typically hypomethylated in immune-enriched tumors. CONCLUSION: SMs are more benign than their intracranial counterparts, and gross-total resection results in long term PFS. Methylation profiling identifies subgroups with differences in clinical variables.

Invention of novel 3-aminopiperidin-2-ones as calcitonin gene-related peptide receptor antagonists.

A novel series of 3-amino-piperidin-2-one-based calcitonin gene-related peptide (CGRP) receptor antagonists was invented based upon the discovery of unexpected structure-activity observations. Initial exploration of the structure-activity relationships enabled the generation of a moderately potent lead structure (4). A series of modifications, including ring contraction and inversion of stereocenters, led to surprising improvements in CGRP receptor affinity. These studies identified compound 23, a structurally novel potent, orally bioavailable CGRP receptor antagonist.

A targeted gene expression biomarker predicts clinic low-risk meningioma recurrence.

BACKGROUND: Despite reassuring clinical and histological features, low grade meningiomas can recur after surgery. Targeted gene expression profiling improves risk stratification of meningiomas, but the utility of this approach for clinical low-risk meningiomas is incompletely understood. METHODS: This was a multicenter retrospective cohort study of meningiomas from patients who were treated at 4 institutions from 1992 to 2023. Adult patients with newly diagnosed or recurrent World Health Organization (WHO) grade 1 meningiomas that were treated with gross total resection (GTR) or subtotal resection (STR), or newly diagnosed WHO grade 2 meningiomas that were treated with GTR, were included. A 34-gene expression biomarker and gene expression risk score (continuous from 0 to 1) was evaluated in all samples. RESULTS: The study cohort was comprised of 723 patients, none of which were used for discovery or training of the gene expression biomarker and 265 of which were previously unreported. There were 626 WHO grade 1 meningiomas, 490 with GTR and 126 with STR, and 97 WHO grade 2 meningiomas with GTR. Targeted gene expression profiling classified 51.3% of clinical low-risk meningiomas as molecular intermediate-risk and 9.5% as molecular high-risk. Combining the gene expression biomarker with extent of resection revealed 19.8% of clinical low-risk meningiomas had unfavorable local freedom from recurrence (LFFR) and overall survival (OS), including 7.1% of newly diagnosed WHO grade 1 meningiomas with GTR. The risk score was prognostic for LFFR (HR per 0.1 increase in risk score 1.89, 95% CI 1.58-2.25) across all WHO grades, extents of resection, and newly diagnosed or recurrent presentations. CONCLUSIONS: Targeted gene expression profiling can identify clinical low-risk meningiomas that are likely to recur after surgery.

The Precision Resuscitation With Crystalloids in Sepsis (PRECISE) Trial: A Trial Protocol.

Importance: Intravenous fluids are an essential part of treatment in sepsis, but there remains clinical equipoise on which type of crystalloid fluids to use in sepsis. A previously reported sepsis subphenotype (ie, group D) has demonstrated a substantial mortality benefit from balanced crystalloids compared with normal saline. Objective: To test the hypothesis that targeting balanced crystalloids to patients with group D sepsis through an electronic health record (EHR) alert will reduce 30-day inpatient mortality. Design, Setting, and Participants: The Precision Resuscitation With Crystalloids in Sepsis (PRECISE) trial is a parallel-group, multihospital, single-blind, pragmatic randomized clinical trial to be conducted at 6 hospitals in the Emory Healthcare system. Patients with suspicion of group D infection in whom a clinician initiates an order for normal saline in the emergency department (ED) or intensive care unit (ICU) will be randomized to usual care and intervention arms. Intervention: An EHR alert that appears in the ED and ICUs to nudge clinicians to use balanced crystalloids instead of normal saline. Main Outcomes and Measures: The primary outcome is 30-day inpatient mortality. Secondary outcomes are ICU admission, in-hospital mortality, receipt of vasoactive drugs, receipt of new kidney replacement therapy, and receipt of mechanical ventilation (vasoactive drugs, kidney replacement therapy, and mechanical ventilation are counted if they occur after randomization and within the 30-day study period). Intention-to-treat analysis will be conducted. Discussion: The PRECISE trial may be one of the first precision medicine trials of crystalloid fluids in sepsis. Using routine vital signs (temperature, heart rate, respiratory rate, and blood pressure), available even in low-resource settings, a validated machine learning algorithm will prospectively identify and enroll patients with group D sepsis who may have a substantial mortality reduction from used of balanced crystalloids compared with normal saline. Results: On finalizing participant enrollment and analyzing the data, the study's findings will be shared with the public through publication in a peer-reviewed journal. Conclusions: With use of a validated machine learning algorithm, precision resuscitation in sepsis could fundamentally redefine international standards for intravenous fluid resuscitation. Trial Registration: ClinicalTrials.gov Identifier: NCT06253585.

Convenient syntheses of 2-acylamino-4-halothiazoles and acylated derivatives using a versatile Boc-intermediate.

The 2-aminothiazole grouping is a significant feature of many series of biologically active molecules, including antibiotics, anticancer agents and NSAIDs. We have a longstanding interest in the synthesis and biological evaluation of thiazolides, viz. [2-hydroxyaroyl-N-(thiazol-2-yl)-amides] which have broad spectrum antiinfective, especially antiviral, properties. However, 2-amino-4-substituted thiazoles, especially 4-halo examples, are not easily available. We now report practical, efficient syntheses of this class from readily available pseudothiohydantoin, or 2-aminothiazol-4(5H)-one: the key intermediate was its Boc derivative, from which, under Appel-related conditions, Br, Cl and I could all be introduced at C(4). Whereas 2-amino-4-Br/4-Cl thiazoles gave low yields of mixed products on acylation, including a bis-acyl product, further acylation of the Boc intermediates, with a final mild deprotection step, afforded the desired thiazolides cleanly and in good yields. In contrast, even mild hydrolysis of 2-acetamido-4-chlorothiazole led to decomposition with fast reversion to 2-aminothiazol-4(5H)-one. We also present a correction of a claimed synthesis of 2-acetamido-4-chlorothiazole, which in fact produces its 5-chloro isomer.

Functional Anatomy and Biomechanics of Shoulder Instability.

The glenohumeral joint is the least congruent and least constrained joint with a complex relationship of static and dynamic stabilizers to balance its native mobility with functional stability. In the young athlete, anterior shoulder instability is multifactorial and can be a challenge to treat, requiring a patient-specific treatment approach. Surgical decision-making must consider patient-specific factors such as age, sport activity and level, underlying ligamentous laxity, and goals for return to activity, in addition to careful scrutiny of the underlying pathology to include humeral and glenoid bone loss and surrounding scapular bone morphology.

Bone augmentation using titanium mesh: A systematic review and meta-analysis.

PURPOSE: To review and compare the available literature on bone regeneration using titanium mesh and map the current evidence on bone gain outcomes and complications while comparing this scaffold with collagen membranes. MATERIALS AND METHODS: A comprehensive electronic and manual search was performed to identify randomised and non-randomised prospective controlled clinical trials that involved the use of titanium mesh in at least one arm, with outcomes including complications and vertical and/or horizontal bone gain. The focused questions were defined as follows: What are the outcomes of using titanium mesh in ridge augmentation compared to other types of barrier membrane, and what is the complication rate (membrane exposure and infection) when titanium mesh is used in these procedures? RESULTS: A total of 22 articles were included in the qualitative analysis. Overall, the studies that measured bone gain resulted in 3.36 mm vertical (196 subjects; 95% confidence interval 2.44 to 4.64 mm, range 1.4 to 5.7 mm) and 3.26 mm horizontal augmentation (81 subjects; 95% confidence interval 2.93 to 3.63 mm, range 2.6 to 3.7 mm), with variability among studies. The most commonly noted complication was mesh exposure, regardless of the type of mesh used, and the second most common was graft failure. The overall pooled complications rate reported in clinical trials was 10.8%. The meta-analysis comparing titanium mesh and collagen membranes, controlling for the type of bone regeneration (staged or simultaneous with implant placement), failed to show a significant difference in horizontal bone gain between the two techniques. CONCLUSIONS: Within the limitations of the present study and acknowledging the heterogeneity among the articles included, titanium mesh can serve as a feasible protective scaffold for bone regeneration with a relatively acceptable complication rate and in defects requiring around 4 mm 3D reconstruction. Data on patient-reported outcomes were scarce. CONFLICT-OF-INTEREST STATEMENT: None of the authors have any financial interests, either directly or indirectly, in the products or information mentioned in the present article.

Prominent tissue hemophagocytic lymphohistiocytosis obscuring primary cutaneous gamma/delta (γδ) T-cell lymphoma.

Primary cutaneous gamma/delta (γδ) T-cell lymphoma (PCGDTCL) is a rare, aggressive malignant neoplasm of γδ T lymphocytes arising within the skin and subcutis. We present a challenging case of PCGDTCL diagnosed in a 35-year-old male soldier who presented with constitutional symptoms, pancytopenia, hemophagocytic lymphohistiocytosis (HLH), disseminated lymphadenopathy, and cutaneous lesions on his extremities and back following a deployment to Iraq and Syria. Histopathologic evaluation of an excisional biopsy showed that PCGDTCL can be focal, localized to the subcutaneous adipose tissue, and obscured by predominant HLH in the surrounding tissues. Pathologists should recognize that the diagnosis of PCGDTCL may be confounded by florid HLH and require multiple biopsies and a comprehensive immunohistochemical panel.

Discovery of 1,3,4-oxadiazoles with slow-action activity against Plasmodium falciparum malaria parasites.

To achieve malaria eradication, new preventative agents that act differently to front-line treatment drugs are needed. To identify potential chemoprevention starting points we screened a sub-set of the CSIRO Australia Compound Collection for compounds with slow-action in vitro activity against Plasmodium falciparum. This work identified N,N-dialkyl-5-alkylsulfonyl-1,3,4-oxadiazol-2-amines as a new antiplasmodial chemotype (e.g., 1 96 h IC50 550 nM; 3 96 h IC50 160 nM) with a different action to delayed-death slow-action drugs. A series of analogues were synthesized from thiotetrazoles and carbomoyl derivatives using Huisgen 1,3,4-oxadiazole synthesis followed by oxidation of the resultant thioethers to target sulfones. Structure activity relationship analysis of analogues identified compounds with potent and selective in vitro activity against drug-sensitive and multi-drug resistant Plasmodium parasites (e.g., 31 and 32 96 h IC50 <40 nM; SI > 2500). Subsequent studies in mice with compound 1, which had the best microsomal stability of the compounds assessed (T1/2 >255 min), demonstrated rapid clearance and poor oral in vivo efficacy in a P. berghei murine malaria model. These data indicate that while N,N-dialkyl-5-alkylsulfonyl-1,3,4-oxadiazol-2-amines are a novel class of slow-acting antiplasmodial agents, the further development of this chemotype for malaria chemoprophylaxis will require pharmacokinetic profile improvements.

Aortic Root Dilation and Genotype Associations in Phelan-McDermid Syndrome.

Phelan-McDermid syndrome (PMS) is a rare genetic neurodevelopmental disorder that results from the loss of one functional copy of the SHANK3 gene. While many clinical features of PMS are well-understood, there is currently limited literature on cardiovascular abnormalities in PMS. This report aims to evaluate the prevalence of aortic root dilation (ARD) among individuals with PMS and to understand if underlying genetic variation relates to risk for ARD. We present findings from 59 participants collected from a multisite observational study evaluating the phenotype and natural history of PMS. Individual echocardiographic and genetic reports were analyzed for aortic root measurements and genetic variant data, respectively. Our a priori hypothesis was that participants with chromosome 22 deletions with hg19 start coordinates on or before 49,900,000 (larger deletions) would have more instances of ARD than participants with deletion start coordinates after 49,900,000 (smaller deletions). Eight participants (14%) had ARD, and its presence was statistically significantly associated with large deletions (p = 0.047). Relatedly, participants with ARD had significantly more genes deleted on chromosome 22 than participants without ARD (p = 0.013). These results could aid in the identification of individuals with PMS who are at higher risk for ARD.

Pediatric glioma immune profiling identifies TIM3 as a therapeutic target in BRAF-Fusion pilocytic astrocytoma.

Despite being the leading cause of childhood mortality, pediatric gliomas have been relatively understudied, and the repurposing of immunotherapies has not been successful. Whole transcriptome sequencing, single-cell sequencing, and sequential multiplex immunofluorescence were used to identify an immunotherapy strategy evaluated in multiple preclinical glioma models. MAPK-driven pediatric gliomas have a higher interferon signature relative to other molecular subgroups. Single-cell sequencing identified an activated and cytotoxic microglia population designated MG-Act in BRAF-fused MAPK-activated pilocytic astrocytoma (PA), but not in high-grade gliomas or normal brain. TIM3 is expressed on MG-Act and on the myeloid cells lining the tumor vasculature but not normal brain. TIM3 expression becomes upregulated on immune cells in the PA microenvironment and anti-TIM3 reprograms ex vivo immune cells from human PAs to a pro-inflammatory cytotoxic phenotype. In a genetically engineered murine model of MAPK-driven low-grade gliomas, anti-TIM3 treatment increased median survival over IgG and anti-PD1 treated mice. ScRNA sequencing data during the therapeutic window of anti-TIM3 demonstrates enrichment of the MG-Act population. The therapeutic activity of anti-TIM3 is abrogated in the CX3CR1 microglia knockout background. These data support the use of anti-TIM3 in clinical trials of pediatric low-grade MAPK-driven gliomas.

Regulated induced proximity targeting chimeras-RIPTACs-A heterobifunctional small molecule strategy for cancer selective therapies.

We describe a protein proximity inducing therapeutic modality called Regulated Induced Proximity Targeting Chimeras or RIPTACs: heterobifunctional small molecules that elicit a stable ternary complex between a target protein (TP) selectively expressed in tumor cells and a pan-expressed protein essential for cell survival. The resulting co-operative protein-protein interaction (PPI) abrogates the function of the essential protein, thus leading to death selectively in cells expressing the TP. This approach leverages differentially expressed intracellular proteins as novel cancer targets, with the advantage of not requiring the target to be a disease driver. In this chemical biology study, we design RIPTACs that incorporate a ligand against a model TP connected via a linker to effector ligands such as JQ1 (BRD4) or BI2536 (PLK1) or CDK inhibitors such as TMX3013 or dinaciclib. RIPTACs accumulate selectively in cells expressing the HaloTag-FKBP target, form co-operative intracellular ternary complexes, and induce an anti-proliferative response in target-expressing cells.

RNA splicing as a biomarker and phenotypic driver of meningioma DNA methylation groups.

BACKGROUND: Advances in our understanding of the molecular biology of meningiomas have led to significant gains in the ability to predict patient prognosis and tumor recurrence and to identify novel targets for therapeutic design. Specifically, classification of meningiomas based on DNA methylation has greatly improved our ability to risk stratify patients, however new questions have arisen in terms of the underlying impact these DNA methylation signatures have on meningioma biology. METHODS: This study utilizes RNA-seq data from 486 meningioma samples corresponding to three meningioma DNA methylation groups (Merlin-intact, Immune-enriched, and Hypermitotic), followed by in vitro experiments utilizing human meningioma cell lines. RESULTS: We identify alterations in RNA splicing between meningioma DNA methylation groups including individual splicing events that correlate with Hypermitotic meningiomas and predict tumor recurrence and overall patient prognosis and compile a set of splicing events that can accurately predict DNA methylation classification based on RNA-seq data. Furthermore, we validate these events using RT-PCR in patient samples and meningioma cell lines. Additionally, we identify alterations in RNA binding proteins and splicing factors that lie upstream of RNA splicing events, including upregulation of SRSF1 in Hypermitotic meningiomas which we show drives alternative RNA splicing changes. Finally, we design splice switching antisense oligonucleotides to target RNA splicing changes in NASP and MFF observed in Hypermitotic meningiomas, providing a rationale for RNA-based therapeutic design. CONCLUSIONS: RNA splicing is an important driver of meningioma phenotypes that can be useful in prognosticating patients and as a potential exploit for therapeutic vulnerabilities.

Using Immersive Virtual Reality to Classify Pediatric Thoracolumbar Spine Injuries.

Objective This study aimed to assess the reliability and reproducibility of the AO Spine Thoracolumbar Injury Classification System by using virtual reality (VR). We hypothesized that VR is a highly reliable and reproducible method to classify traumatic spine injuries. Methods VR 3D models were created from CT scans of 26 pediatric patients with thoracolumbar spine injuries. Seven orthopedic trainees were educated on the VR platform and AO Spine Thoracolumbar Injury Classification System. Classifications were summarized by primary class and subclass for both rater readings performed two weeks apart with image order randomized. Intra-observer reproducibility was quantified by Fleiss's kappa (kF) for primary classifications and Krippendorff's alpha (aK) for subclassifications along with 95% confidence intervals (CIs) for each rater and across all raters. Inter-observer reliability was quantified by kF for primary classifications and aK for subclassifications along with 95% CIs across all raters for the first read, the second read, and all reads combined. The interpretations were as follows: 0-0.2: slight; 0.2-0.4: fair; 0.4-0.6: moderate; 0.6-0.8: substantial; and >0.8: almost perfect agreement. Results A total of 364 classifications were submitted by seven raters. Intra-observer reproducibility ranged from moderate (kF=0.55) to almost perfect (kF=0.94) for primary classifications and from substantial (aK=0.68) to almost perfect (aK=0.91) for subclassifications. Reproducibility was substantial across all raters for the primary class (kF=0.71; 95% CI=0.61-9.82) and subclass (aK=0.79; 95% CI=0.69-0.86). Inter-observer reliability was substantial (kF=0.63; 95% CI=0.57-0.69) for the first read, moderate (kF=0.58; 95% CI=0.52-0.64) for the second read, and substantial (kF=0.61; 95% CI=0.56-0.65) for all reads for primary classifications. For subclassifications, inter-observer reliability was substantial (aK=0.74; 95% CI=0.58-0.83) for the first read, second read (aK=0.70; 95% CI=0.53-0.80), and all reads (aK=0.72; 95% CI=0.60-0.79). Conclusions Based on our findings, VR is a reliable and reproducible method for the classification of pediatric spine trauma, besides its ability to function as an educational tool for trainees. Further research is needed to evaluate its application for other spine conditions.

Chemical Trends of the Bulk and Surface Termination-Dependent Electronic Structure of Metal-Intercalated Transition Metal Dichalcogenides.

The addition of metal intercalants into the van der Waals gaps of transition metal dichalcogenides has shown great promise as a method for controlling their functional properties. For example, chiral helimagnetic states, current-induced magnetization switching, and a giant valley-Zeeman effect have all been demonstrated, generating significant renewed interest in this materials family. Here, we present a combined photoemission and density-functional theory study of three such compounds: , , and , to investigate chemical trends of the intercalant species on their bulk and surface electronic structure. Our resonant photoemission measurements indicate increased hybridization with the itinerant NbS2-derived conduction states with increasing atomic number of the intercalant, leading to pronounced mixing of the nominally localized intercalant states at the Fermi level. Using spatially and angle-resolved photoemission spectroscopy, we show how this impacts surface-termination-dependent charge transfers and leads to the formation of new dispersive states of mixed intercalant-Nb character at the Fermi level for the intercalant-terminated surfaces. This provides an explanation for the origin of anomalous states previously reported in this family of compounds and paves the way for tuning the nature of the magnetic interactions in these systems via control of the hybridization of the magnetic ions with the itinerant states.

Accuracy and Outcomes of a Novel Cut-Block Positioning Robotic-Arm Assisted System for Total Knee Arthroplasty: A Systematic Review and Meta-Analysis.

Background: The primary objective of this study was to determine the accuracy and precision of component positioning of the ROSA Robotic System for total knee arthroplasty (TKA). Methods: A Preferred Reporting Items for Systematic Reviews and Meta-Analysis systematic review was conducted using 4 electronic databases (MEDLINE, EMBASE, Pubmed, and Cochrane Library) to identify all clinical and radiological studies reporting information about the use and results of the ROSA system. The criteria for inclusion were published research articles evaluating the accuracy of component positioning, learning curve, component alignment, complications, and functional outcomes in adults who underwent robotic-assisted TKA. The National Institutes of Health Quality Assessment Tool was used to evaluate the quality of all the included studies. Results: A total of 26 studies were assessed for eligibility, and 17 met the inclusion criteria. Nine studies reported on the accuracy and precision of component positioning. The ROSA platform for TKA had a cutting error of less than 0.6° for all coronal and sagittal parameters. Pooled analysis demonstrated accuracy within 0.61-1.87° and precision within 0.97-1.34° when the final intraoperative plan was compared to postoperative radiographs with fewer outliers. Four studies reported improved functional scores with ROSA-assisted TKA than conventional TKA within 1 year of surgery. There was no difference in overall complication rates when compared to conventional TKA. Conclusions: The ROSA system is both highly accurate and precise, with fewer outliers when analyzed at various time points, including postoperative standing radiographs. Future studies with robust methodology and longer follow-up are required to demonstrate whether these findings have any clinical benefits in the long term.

Development of Ligands and Degraders Targeting MAGE-A3.

Type I melanoma antigen (MAGE) family members are detected in numerous tumor types, and expression is correlated with poor prognosis, high tumor grade, and increased metastasis. Type I MAGE proteins are typically restricted to reproductive tissues, but expression can recur during tumorigenesis. Several biochemical functions have been elucidated for them, and notably, MAGEs regulate proteostasis by serving as substrate recognition modules for E3 ligase complexes. The repertoire of E3 ligase complexes that can be hijacked for targeted protein degradation continues to expand, and MAGE-E3 complexes are an especially attractive platform given their cancer-selective expression. Additionally, type I MAGE-derived peptides are presented on cancer cell surfaces, so targeted MAGE degradation may increase antigen presentation and improve immunotherapy outcomes. Motivated by these applications, we developed novel, small-molecule ligands for MAGE-A3, a type I MAGE that is widely expressed in tumors and associates with TRIM28, a RING E3 ligase. Chemical matter was identified through DNA-encoded library (DEL) screening, and hit compounds were validated for in vitro binding to MAGE-A3. We obtained a cocrystal structure with a DEL analog and hypothesize that the small molecule binds at a dimer interface. We utilized this ligand to develop PROTAC molecules that induce MAGE-A3 degradation through VHL recruitment and inhibit the proliferation of MAGE-A3 positive cell lines. These ligands and degraders may serve as valuable probes for investigating MAGE-A3 biology and as foundations for the ongoing development of tumor-specific PROTACs.