We Are Not "DON" YET: Discovery of Tumor Targeted Glutamine Antagonists Through Prodrug Strategy | Dr. Rana Rais

Many cancers change their energy metabolic requirements and become "glutamine addicted" for their growth and survival. The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) has shown robust efficacy in both preclinical animal models and exploratory clinical studies. Although promising, clinical studies with DON were halted due to its marked dose-limiting toxicities, which were mainly gastrointestinal (GI)-related, as the GI system is highly dependent on glutamine utilization. To overcome these toxicity issues, we sought to develop a DON prodrug that could selectively deliver DON to tumor tissues while sparing normal glutamine-dependent tissues like the GI tract. We designed over 100 prodrugs by installing dual promoeities on DON that can be dislodged by the enriched milieu of esterase and protease enzymes in tumor. Using iterative chemistry and pharmacokinetic efforts, we identified various promising DON prodrugs that showed preferential tumor bioactivation and delivery. Of these, our best DON prodrug, DRP-104 is bio-activated in the tumor while bio-inactivated in gastrointestinal (GI) tissues resulting in 11-fold higher glutamine antagonist delivery to the tumor (target site) versus GI (toxicity site) resulting in robust anti-cancer activity with minimal GI-toxicities. DRP-104, is now being evaluated in Ph1/2a clinical trials in cancer patients (ClinicalTrials.gov Identifier: NCT04471415).

References:
Leone et al., Science 366, 1013-1021 (2019)
Rais et al., Sci. Adv. 8, eabq5925 (2022)