A5090359406- Cancer, Hypoxia, and Metabolism
- Immune cells in cancer
- Cancer Research and Treatments
- Glioma Diagnosis and Treatment
- Neuroblastoma Research and Treatments
- Receptor Mechanisms and Signaling
- Neurofibromatosis and Schwannoma Cases
- Epigenetics and DNA Methylation
- Neuroinflammation and Neurodegeneration Mechanisms
- Neurotransmitter Receptor Influence on Behavior
- Neuropeptides and Animal Physiology
- Neuroscience and Neuropharmacology Research
- Extracellular vesicles in disease
- Pain Mechanisms and Treatments
- Sphingolipid Metabolism and Signaling
- Pharmacological Receptor Mechanisms and Effects
- Nanoparticle-Based Drug Delivery
- Amino Acid Enzymes and Metabolism
- Sarcoma Diagnosis and Treatment
- Radiopharmaceutical Chemistry and Applications
- Drug Transport and Resistance Mechanisms
- Tryptophan and brain disorders
- Adenosine and Purinergic Signaling
- Biochemical and Molecular Research
- Helicobacter pylori-related gastroenterology studies
Johns Hopkins University
2016-2025
Johns Hopkins Medicine
2015-2024
University Hospital of Bern
2023
National Institute on Drug Abuse
2020-2023
Universitat Autònoma de Barcelona
2023
Universitat de Barcelona
2023
Institut de Biomedicina de la Universitat de Barcelona
2023
University of Baltimore
2016-2023
Drug Discovery Laboratory (Norway)
2016-2020
University of Alabama at Birmingham
2020
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...
Myeloid cells comprise a major component of the tumor microenvironment (TME) that promotes growth and immune evasion. By employing small-molecule inhibitor glutamine metabolism, not only were we able to inhibit growth, but markedly inhibited generation recruitment myeloid-derived suppressor (MDSCs). Targeting metabolism led decrease in CSF3 hence MDSCs as well immunogenic cell death, leading an increase inflammatory tumor-associated macrophages (TAMs). Alternatively, inhibiting themselves...
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...
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
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...
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...
Hookworm inspired, autonomous latching on the gastrointestinal mucosa extends in vivo retention of a drug delivery device.
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...
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),...
The recent and precipitous increase in opioid analgesic abuse overdose has inspired investigation of the dopamine D3 receptor (D3R) as a target for therapeutic intervention. Metabolic instability or predicted toxicity precluded successful translation previously reported D3R-selective antagonists to clinical use cocaine abuse. Herein, we report series novel D3R crystal structure-guided 4-phenylpiperazines with exceptionally high affinities and/or selectivities varying efficacies. Lead...
The development of pharmacotherapeutic treatments psychostimulant abuse has remained a challenge, despite significant efforts made toward relevant mechanistic targets, such as the dopamine transporter (DAT). atypical DAT inhibitors have received attention due to their promising pharmacological profiles in animal models cocaine and methamphetamine abuse. Herein, we report series modafinil analogues that an inhibitor profile. We extended SAR by chemically manipulating oxidation states...
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...
Brain injury and inflammation induces a local release of extracellular vesicles (EVs) from astrocytes carrying proteins, RNAs, microRNAs into the circulation. When these reach liver, they stimulate secretion cytokines that mobilize peripheral immune cell infiltration brain, which can cause secondary tissue damage impair recovery. Recent studies suggest suppression EV biosynthesis through neutral sphingomyelinase 2 (nSMase2) inhibition may represent new therapeutic strategy. Unfortunately,...
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...
Almost half of HIV-positive people on antiretroviral therapy have demonstrable mild neurocognitive impairment (HIV-NCI), even when virologically suppressed. Intranasal insulin improves cognition in Alzheimer's disease and diabetes. Here we tested intranasal a model HIV-NCI EcoHIV-infected conventional mice.Insulin pharmacokinetics following administration to mice was determined by ELISA. Mice were inoculated with EcoHIV cause NCI; 23 days or 3 months after infection they treated daily for 9...
Metabolic reprogramming is a common feature in cancer, and it critical to facilitate cancer cell growth. Isocitrate Dehydrogenase 1/2 (IDH1 IDH2) mutations (IDHmut) are the most genetic alteration glioma grade II III secondary glioblastoma these increase reliance on glutamine metabolism, suggesting potential vulnerability. In this study, we tested hypothesis that brain penetrant antagonist prodrug JHU-083 reduces growth.We performed growth, cycle, protein expression deprived or Glutaminase...