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Autor
Aguilar, Joanna Marie H 1 Alt, Jesse 1 Arwood, Matthew L 1 Dash, Ranjeet P 1 Lam, Jenny 1 Lemberg, Kathryn M 1 Leone, Robert D 1 Majer, Pavel 1 Pal, Arindom 1 Pandey, Rajeev 1 Peters, Diane E 1 Powell, Jonathan D 1 Rais, Rana 1 Seiwert, Tanguy 1 Slusher, Barbara S 1 Tallon, Carolyn 1 Tenora, Lukáš 1 Thomas, Ajit G 1 Wu, Ying 1 Zhao, Liang 1
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Pracoviště
Department of Medicine Johns Hopkins ... 1 Department of Neurology Johns Hopkins... 1 Department of Neuroscience Johns Hopk... 1 Department of Oncology Johns Hopkins ... 1 Department of Pharmacology and Molecu... 1 Department of Psychiatry and Behavior... 1 Institute of Organic Chemistry and Bi... 1 Johns Hopkins Drug Discovery Johns Ho... 1 The Bloomberg Kimmel Institute for Ca... 1
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Autor
Aguilar, Joanna Marie H 1 Alt, Jesse 1 Arwood, Matthew L 1 Dash, Ranjeet P 1 Lam, Jenny 1 Lemberg, Kathryn M 1 Leone, Robert D 1 Majer, Pavel 1 Pal, Arindom 1 Pandey, Rajeev 1 Peters, Diane E 1 Powell, Jonathan D 1 Rais, Rana 1 Seiwert, Tanguy 1 Slusher, Barbara S 1 Tallon, Carolyn 1 Tenora, Lukáš 1 Thomas, Ajit G 1 Wu, Ying 1 Zhao, Liang 1
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Pracoviště
Department of Medicine Johns Hopkins ... 1 Department of Neurology Johns Hopkins... 1 Department of Neuroscience Johns Hopk... 1 Department of Oncology Johns Hopkins ... 1 Department of Pharmacology and Molecu... 1 Department of Psychiatry and Behavior... 1 Institute of Organic Chemistry and Bi... 1 Johns Hopkins Drug Discovery Johns Ho... 1 The Bloomberg Kimmel Institute for Ca... 1
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Rais, Rana
Autor Rais, Rana ORCID Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
- Lemberg, Kathryn M
- Tenora, Lukáš
- Arwood, Matthew L
- Pal, Arindom
- Alt, Jesse
- Wu, Ying
- Lam, Jenny
- Aguilar, Joanna Marie H
- Zhao, Liang
NLK
Directory of Open Access Journals
od 2015
Freely Accessible Science Journals
od 2015
PubMed Central
od 2015
Europe PubMed Central
od 2015
Open Access Digital Library
od 2015-01-01
Open Access Digital Library
od 2015-01-01
ROAD: Directory of Open Access Scholarly Resources
od 2015
PubMed
36383674
DOI
10.1126/sciadv.abq5925
Knihovny.cz E-zdroje
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+ T cells. DON showed promising efficacy in clinical trials; however, its development was halted by dose-limiting gastrointestinal (GI) toxicities. Given its clinical potential, we designed DON peptide prodrugs and found DRP-104 [isopropyl(S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)-propanamido)-6-diazo-5-oxo-hexanoate] that was preferentially bioactivated to DON in tumor while bioinactivated to an inert metabolite in GI tissues. In drug distribution studies, DRP-104 delivered a prodigious 11-fold greater exposure of DON to tumor versus GI tissues. DRP-104 affected multiple metabolic pathways in tumor, including decreased glutamine flux into the TCA cycle. In efficacy studies, both DRP-104 and DON caused complete tumor regression; however, DRP-104 had a markedly improved tolerability profile. DRP-104's effect was CD8+ T cell dependent and resulted in robust immunologic memory. DRP-104 represents a first-in-class prodrug with differential metabolism in target versus toxicity tissue. DRP-104 is now in clinical trials under the FDA Fast Track designation.
- MeSH
- CD8-pozitivní T-lymfocyty metabolismus MeSH
- diazooxonorleucin farmakologie terapeutické užití MeSH
- glutamin metabolismus MeSH
- inhibitory enzymů terapeutické užití MeSH
- lidé MeSH
- nádory * farmakoterapie MeSH
- prekurzory léčiv * farmakologie terapeutické užití MeSH
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- lidé MeSH
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- časopisecké články MeSH
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