Discovery of DRP-104, a tumor-targeted metabolic inhibitor prodrug

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

Discovery of DRP-104, a tumor-targeted metabolic inhibitor prodrug

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

Discovery of DRP-104, a tumor-targeted metabolic inhibitor prodrug

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10401 - Organic chemistry

Projekt

<a href="/cs/project/LTAUSA18166" target="_blank" >LTAUSA18166: Nádorově cílená proléčiva glutaminových antagonistů</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2022

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Science Advances

ISSN

2375-2548

e-ISSN

2375-2548

Svazek periodika

8

Číslo periodika v rámci svazku

46

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

16

Strana od-do

eabq5925

Kód UT WoS článku

000945384000007

EID výsledku v databázi Scopus

2-s2.0-85142402033