PR-104

PR-104 is a small-molecule phosphate ester dinitrobenzamide mustard pre-prodrug from the class of hypoxia-activated prodrugs (HAPs), developed as a potential anti-cancer therapeutic agent by Proacta. After intravenous administration, it is rapidly hydrolyzed in vivo to its cognate alcohol form, PR-104A. In hypoxic cells—such as those found in solid tumors—PR-104A undergoes one-electron reduction by NADPH:cytochrome P450 oxidoreductase and other reductases to generate cytotoxic hydroxylamine (PR-104H) and amine (PR-104M) metabolites. These metabolites are DNA cross-linking agents that induce cell death by inhibiting DNA repair and synthesis, leading to cell-cycle arrest and apoptosis in hypoxic tumor cells. Additionally, PR-104A can be activated independently of oxygen by aldo-keto reductase 1C3 (AKR1C3), which is upregulated in some cancers such as certain leukemias. This off-target activation can lead to myelotoxicity due to effects on bone marrow progenitors. Preclinical studies have shown marked antitumor activity both as monotherapy and combined with radiotherapy or chemotherapy. Clinical trials have explored its use primarily for advanced solid tumors and relapsed/refractory acute leukemias.

Other names

3,5-dinitrobenzamide nitrogen mustard pre-prodrug