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molecules of the month

sirpiglenastat

IV/SC glutamine antimetabolite prodrug

Ph. I/IIa in advanced solid tumors

dual prodrug of natural product

Sci. Adv., 16 November 2022

Johns Hopkins / Dracen Pharmaceuticals

sirpiglenastat chemical structure IV/SC glutamine antimetabolite prodrug- Johns Hopkins / Dracen Pharmaceuticals
3 mins read

A first-in-class diazo-prodrug for the treatment of solid tumors. Sirpiglenastat (DRP-104) (Johns Hopkins/Dracen Pharmaceuticals) is a dual prodrug of 6-diazo-5-oxo-l-norleucine (DON), a diazoketone-based glutamine irreversible antagonist used to suppress cancer cell metabolism. Rapidly growing cancer cells depend on glutamine as an energy source via the tricarboxylic acid (TCA) cycle, as well as a carbon and nitrogen source for biosynthesis and cellular homeostasis. Thus, approaches to blocking glutamine uptake or metabolism, such as glutaminase inhibitors like telaglenastat (Calithera, Ph. I/II) have been investigated. Although DON itself demonstrated promising preclinical and clinical efficacy, the program was terminated due to dose-limiting gastrointestinal (GI) toxicities. As a dual prodrug that is selectively activated in tumor cells and deactivated in GI tissues, sirpiglenastat has a…


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