Rais_2022_Sci.Adv_8_eabq5925

Reference

Title : Discovery of DRP-104, a tumor-targeted metabolic inhibitor prodrug - Rais_2022_Sci.Adv_8_eabq5925
Author(s) : Rais R , Lemberg KM , Tenora L , Arwood ML , Pal A , Alt J , Wu Y , Lam J , Aguilar JMH , Zhao L , Peters DE , Tallon C , Pandey R , Thomas AG , Dash RP , Seiwert T , Majer P , Leone RD , Powell JD , Slusher BS
Ref : Sci Adv , 8 :eabq5925 , 2022
Abstract :

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.

PubMedSearch : Rais_2022_Sci.Adv_8_eabq5925
PubMedID: 36383674

Related information

Substrate Sirpiglenastat

Citations formats

Rais R, Lemberg KM, Tenora L, Arwood ML, Pal A, Alt J, Wu Y, Lam J, Aguilar JMH, Zhao L, Peters DE, Tallon C, Pandey R, Thomas AG, Dash RP, Seiwert T, Majer P, Leone RD, Powell JD, Slusher BS (2022)
Discovery of DRP-104, a tumor-targeted metabolic inhibitor prodrug
Sci Adv 8 :eabq5925

Rais R, Lemberg KM, Tenora L, Arwood ML, Pal A, Alt J, Wu Y, Lam J, Aguilar JMH, Zhao L, Peters DE, Tallon C, Pandey R, Thomas AG, Dash RP, Seiwert T, Majer P, Leone RD, Powell JD, Slusher BS (2022)
Sci Adv 8 :eabq5925