Table 3 Preclinical Features of DON Prodrug.
From: Exploring the metabolic signaling network of GFPT in cancer
DON prodrug | Plasma stability | Distribution to tumor /CNS | Effect and activation | Tolerability and toxicity | References |
|---|---|---|---|---|---|
Compound 5 | Specie-specific stability | Specific for brain delivery. 10-fold higher than DON | Promising antitumor activity in brain tumors | Not Determined | [205] |
JHU083 | Stable | Tumor-specific and CNS delivery with micromolar brain concentration | Robust antitumor activity, immune activation, and apoptotic induction | Orally bioavailable and very tolerable. No significant gastrointestinal toxicity at the therapeutic dose | |
JHU395 | Stable | Tumor-specific and CNS delivery >2-fold tumor/plasma ratio compared to DON | Robust antitumor activity with apoptotic induction | Orally bioavailable and very tolerable. No significant gastrointestinal toxicity at the therapeutic dose | |
Compound 6 | Stable | Tumor-specific delivery. 6-fold higher tumor exposure of DON than plasma | Tumor-specific bioactivation with in vitro antiproliferative effect | Very Tolerable. Minimal DON release in G1 tissues and consequent limitation in G1 toxicity | [206] |
Prodrug 1/2/3 | Stable | Tumor-specific and CNS delivery | Tumor-specific bioactivation with antitumor effect | Tolerable. Minimal DON release in G1 tissues and limited toxicity at the effective therapeutic doses | [198] |
DRP104 | Stable in humans and in CES1-/- mice | Preferential tumor delivery. 6-fold higher tumor exposure of DON than plasma | Tumor-specific bioactivation. Robust antitumor effect with complete tumor regression and immune activation. | Very tolerable. Negligible DON exposure to G1 and plasma. Reduced toxicity | [209] |
Compound 11 (Optimized DRP104) | Stable in humans and CES1-/- mice | Preferential tumor delivery. 3.6-fold higher tumor exposure of DON than plasma | Tumor-specific bioactivation with in vitro antiproliferative effect. | Not Determined | [217] |
Azo-DON | Stable | Tumor-specific delivery | Hypoxia-specific bioactivation. Enhances antitumor immunity and apoptosis. | Dosage-dependent tolerability. | [210] |
