| First Author | Rais R | Year | 2022 |
| Journal | Sci Adv | Volume | 8 |
| Issue | 46 | Pages | eabq5925 |
| PubMed ID | 36383674 | Mgi Jnum | J:331963 |
| Mgi Id | MGI:7397733 | Doi | 10.1126/sciadv.abq5925 |
| Citation | Rais R, et al. (2022) Discovery of DRP-104, a tumor-targeted metabolic inhibitor prodrug. Sci Adv 8(46):eabq5925 |
| abstractText | 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. |
