A5056312293- Cancer, Hypoxia, and Metabolism
- Cancer Research and Treatments
- Immune cells in cancer
- Glioma Diagnosis and Treatment
- Neuroblastoma Research and Treatments
- Chromatin Remodeling and Cancer
- Neurofibromatosis and Schwannoma Cases
- Epigenetics and DNA Methylation
- Amino Acid Enzymes and Metabolism
- Neuroscience and Neuropharmacology Research
- Nanoparticle-Based Drug Delivery
- Neuropeptides and Animal Physiology
- Sarcoma Diagnosis and Treatment
- Neuroinflammation and Neurodegeneration Mechanisms
- interferon and immune responses
- Biochemical and Molecular Research
- Radiopharmaceutical Chemistry and Applications
- Cancer Mechanisms and Therapy
- Pain Mechanisms and Treatments
- Research on Leishmaniasis Studies
- Protein Degradation and Inhibitors
- Histone Deacetylase Inhibitors Research
- Metabolism and Genetic Disorders
- Tryptophan and brain disorders
- Sphingolipid Metabolism and Signaling
Johns Hopkins University
2015-2025
Johns Hopkins Medicine
2009-2024
University of Baltimore
2018-2023
University Hospital of Bern
2023
National Institutes of Health
2020
United States Department of Health and Human Services
2020
Drug Discovery Laboratory (Norway)
2020
University of Alabama at Birmingham
2020
National Institute on Drug Abuse
2020
Eisai (United States)
2008-2014
The metabolic characteristics of tumors present considerable hurdles to immune cell function and cancer immunotherapy. Using a glutamine antagonist, we metabolically dismantled the immunosuppressive microenvironment tumors. We demonstrate that blockade in tumor-bearing mice suppresses oxidative glycolytic metabolism cells, leading decreased hypoxia, acidosis, nutrient depletion. By contrast, effector T cells responded antagonism by markedly up-regulating adopting long-lived, highly activated...
Targeting glutamine metabolism via pharmacological inhibition of glutaminase has been translated into clinical trials as a novel cancer therapy, but available drugs lack optimal safety and efficacy. In this study, we used proprietary emulsification process to encapsulate bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES), selective relatively insoluble inhibitor, in nanoparticles. BPTES nanoparticles demonstrated improved pharmacokinetics efficacy compared with...
In Brief BACKGROUND: Palonosetron is a 5-HT3-receptor antagonist (5-HT3-RA) that has been shown to be superior other 5-HT3-RAs in phase III clinical trials for the prevention of acute, delayed, and overall chemotherapy-induced nausea vomiting. The improved efficacy palonosetron may due, part, its more potent binding longer half-life. However, these attributes alone are not sufficient explain results with palonosetron. We sought elucidate additional differences among could help observations...
Accurate assessment of gonadal steroid levels in the developing brain is critical for understanding naturally occurring steroid-mediated sexual differentiation as well determining physiological relevance exogenous treatments commonly used study this phenomenon. Using RIA, we measured estradiol (E(2)) content six regions immediately post partum, 1 d and after injection benzoate, testosterone propionate, or aromatase inhibitor formestane. We found sexually dimorphic E(2) several newborn brain....
Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) is a potent and selective allosteric inhibitor of kidney-type glutaminase (GLS) that has served as molecular probe to determine the therapeutic potential GLS inhibition. In an attempt identify more inhibitors with improved drug-like properties, series BPTES analogs were synthesized evaluated. Our structure-activity relationship (SAR) studies revealed some truncated retained potency BPTES, presenting opportunity improve its...
Palonosetron is the only 5-HT<sub>3</sub> receptor antagonist approved for treatment of delayed chemotherapy-induced nausea and vomiting (CINV) in moderately emetogenic chemotherapy. Accumulating evidence suggests that substance P (SP), endogenous ligand acting preferentially on neurokinin-1 (NK-1) receptors, not serotonin (5-HT), dominant mediator emesis. However, palonosetron does bind to NK-1 receptor. Recent data have revealed cross-talk between 5HT<sub>3</sub> signaling pathways; we...
The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON, 1) has shown robust anticancer efficacy in preclinical and clinical studies, but its development was halted due to marked systemic toxicities. Herein we demonstrate that DON inhibits metabolism provides antitumor a murine model of glioblastoma, although toxicity observed. To enhance DON's therapeutic index, utilized prodrug strategy increase brain delivery limit exposure. Unexpectedly, simple alkyl ester-based prodrugs were...
6-Diazo-5-oxo-l-norleucine (DON) is a glutamine antagonist that suppresses cancer cell metabolism but concurrently enhances the metabolic fitness of tumor CD8
Abstract Glutamine metabolism in tumor microenvironments critically regulates antitumor immunity. Using the glutamine-antagonist prodrug JHU083, we report potent growth inhibition urologic tumors by JHU083-reprogrammed tumor-associated macrophages (TAMs) and tumor-infiltrating monocytes. We show JHU083-mediated glutamine antagonism induced TNF, proinflammatory, mTORC1 signaling intratumoral TAM clusters. TAMs also exhibited increased cell phagocytosis diminished proangiogenic capacities. In...
Abstract Glucosinolates (GS) are metabolized to isothiocyanates that may enhance human healthspan by protecting against a variety of chronic diseases. Moringa oleifera , the drumstick tree, produces unique GS but little is known about variation within M . and even less in 12 other species, some which very rare. We assess leaf, seed, stem, leaf gland exudate content 13 species. describe 2 previously unidentified as major components 6 reporting on presence simple alkyl 4 dominant longituba...
A subset of poor-prognosis medulloblastoma has genomic amplification MYC. MYC regulates glutamine metabolism in multiple cellular contexts. We modified the analog 6-diazo-5-oxo-l-norleucine (DON) to mask its carboxylate and amine functionalities, creating a prodrug termed JHU-083 with increased oral bioavailability. hypothesized that this would kill MYC-expressing medulloblastoma. treatment caused decreased growth apoptosis human cell lines. generated mouse MYC-driven model by transforming...
Half of all patients with multiple sclerosis (MS) experience cognitive impairment, for which there is no pharmacological treatment. Using magnetic resonance spectroscopy (MRS), we examined metabolic changes in the hippocampi MS patients, compared findings to performance on a neurocognitive test battery, and found that N -acetylaspartylglutamate (NAAG) concentration correlated functioning. Specifically, impairment had low hippocampal NAAG levels, whereas those normal cognition demonstrated...
Aberrant excitatory neurotransmission associated with overproduction of glutamate has been implicated in the development HIV-associated neurocognitive disorders (HAND). The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON, 14) attenuates synthesis HIV-infected microglia/macrophages, offering therapeutic potential for HAND. We show that 14 prevents manifestation spatial memory deficits chimeric EcoHIV-infected mice, a model is not clinically available, however, because its was hampered by...
6-Diazo-5-oxo-l-norleucine (DON) is a glutamine antagonist with robust anticancer efficacy; however, its therapeutic potential was hampered by biodistribution and toxicity to normal tissues, specifically gastrointestinal (GI) tissues. To circumvent DON's toxicity, we synthesized series of tumor-targeted DON prodrugs designed circulate inert in plasma preferentially activate over tumor. Our best prodrug 6 (isopropyl...
Cytotoxic neuronal swelling and glutamate excitotoxicity are two hallmarks of ischemic stroke. However, the underlying molecular mechanisms not well understood. Here, it is reported that SWELL1, essential subunit volume-regulated anion channel (VRAC), plays a dual role in injury by promoting excitotoxicity. SWELL1 expression upregulated neurons astrocytes after experimental stroke mice. The activated intracellular hypertonicity, leading to Cl
Itaconate, an endogenous immunomodulator from the tricarboxylic acid (TCA) cycle, shows therapeutic effects in various disease models, but is highly polar with poor cellular permeability. We previously reported a novel, topical itaconate derivative, SCD-153, for treatment of alopecia areata. Here, we present discovery orally available derivatives systemic and skin disorders. Four sets prodrugs were synthesized using pivaloyloxymethyl (POM), isopropyloxycarbonyloxymethyl (POC),...
Several 2'-fluorinated tetrahydrouridine derivatives were synthesized as inhibitors of cytidine deaminase (CDA). (4R)-2'-Deoxy-2',2'-difluoro-3,4,5,6-tetrahydrouridine (7a) showed enhanced acid stability over (THU) 5 at its N-glycosyl bond. As a result, compound 7a an improved oral pharmacokinetic profile with higher and more reproducible plasma exposure in rhesus monkeys compared to 5. Co-administration decitabine, CDA substrate, boosted the levels decitabine monkeys. These results...
Abstract As one of the most successful human pathogens, Mycobacterium tuberculosis ( Mtb ) has evolved a diverse array determinants to subvert host immunity and alter metabolic patterns. However, mechanisms pathogen interference with metabolism remain poorly understood. Here we show that glutamine antagonist, JHU083, inhibits proliferation in vitro vivo. JHU083-treated mice exhibit weight gain, improved survival, 2.5 log lower lung bacillary burden at 35 days post-infection, reduced...
A series of 2-substituted 6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione derivatives were synthesized as inhibitors D-amino acid oxidase (DAAO). Many compounds in this found to be potent DAAO inhibitors, with IC50 values the double-digit nanomolar range. The pharmacophore appears metabolically resistant O-glucuronidation unlike other structurally related inhibitors. Among them, 6-hydroxy-2-(naphthalen-1-ylmethyl)-1,2,4-triazine-3,5(2H,4H)-dione 11h was selective over a number targets and orally...