Discovery of DRP-104, a tumor-targeted metabolic inhibitor prodrug
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F22%3A00565069" target="_blank" >RIV/61388963:_____/22:00565069 - isvavai.cz</a>
Result on the web
<a href="https://doi.org/10.1126/sciadv.abq5925" target="_blank" >https://doi.org/10.1126/sciadv.abq5925</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1126/sciadv.abq5925" target="_blank" >10.1126/sciadv.abq5925</a>
Alternative languages
Result language
angličtina
Original language name
Discovery of DRP-104, a tumor-targeted metabolic inhibitor prodrug
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10401 - Organic chemistry
Result continuities
Project
<a href="/en/project/LTAUSA18166" target="_blank" >LTAUSA18166: Tumor targeted prodrugs of glutamine antagonists</a><br>
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2022
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Science Advances
ISSN
2375-2548
e-ISSN
2375-2548
Volume of the periodical
8
Issue of the periodical within the volume
46
Country of publishing house
US - UNITED STATES
Number of pages
16
Pages from-to
eabq5925
UT code for WoS article
000945384000007
EID of the result in the Scopus database
2-s2.0-85142402033