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Discovery of DRP-104, a tumor-targeted metabolic inhibitor prodrug
Rana Rais1,2,3, Kathryn M Lemberg1,4, Lukáš Tenora1,5
1Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
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.
Insights
A novel prodrug, DRP-104, delivers the cancer drug 6-Diazo-5-oxo-l-norleucine (DON) preferentially to tumors. This approach enhances anti-tumor immunity while reducing gastrointestinal toxicities, showing promise in clinical trials.
Area of Science:
- Oncology
- Cancer Immunology
- Drug Development
Background:
- 6-Diazo-5-oxo-l-norleucine (DON) is a glutamine antagonist with anti-cancer properties.
- DON's clinical development was limited by dose-limiting gastrointestinal toxicities.
- Tumor CD8+ T cells benefit metabolically from DON, suggesting therapeutic potential.
Purpose of the Study:
- To design a prodrug of DON that is preferentially activated in tumors and inactivated in gastrointestinal tissues.
- To evaluate the tumor-specific delivery, efficacy, and safety profile of the novel prodrug DRP-104.
Main Methods:
- Synthesis and characterization of the DON prodrug DRP-104.
- Pharmacokinetic studies to assess drug distribution in tumor versus gastrointestinal tissues.
- In vivo efficacy studies in tumor models, evaluating tumor regression and immune responses.
- Assessment of DRP-104's metabolic effects on tumor cells and immune cells.
Main Results:
- DRP-104 demonstrated an 11-fold greater exposure of DON in tumor tissue compared to gastrointestinal tissue.
- DRP-104 effectively suppressed tumor metabolism, including glutamine flux into the TCA cycle.
- Both DRP-104 and DON achieved complete tumor regression, but DRP-104 exhibited a significantly improved tolerability profile.
- DRP-104's anti-tumor efficacy was dependent on CD8+ T cells and induced robust immunologic memory.
Conclusions:
- DRP-104 is a first-in-class prodrug with differential metabolism, enabling targeted DON delivery to tumors.
- This prodrug strategy overcomes the dose-limiting toxicities of DON, enhancing its therapeutic window.
- DRP-104 shows significant promise for cancer treatment and is currently in clinical trials under FDA Fast Track designation.
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