Irofulven (DB05786): A Comprehensive Monograph on a Resurrected Antineoplastic Agent

Executive Summary

Irofulven is a novel, first-in-class, semisynthetic antineoplastic agent belonging to the acylfulvene family of experimental cancer drugs. Its development represents a compelling narrative in modern oncology, tracing its origins from a highly toxic natural product to a potential precision therapeutic. The compound is a structural analog of illudin S, a sesquiterpene toxin isolated from the poisonous and bioluminescent fungus Omphalotus illudens, commonly known as the Jack O'Lantern mushroom.[1] The parent compound, illudin S, exhibited potent antitumor activity but was deemed too toxic for clinical use, prompting a successful medicinal chemistry campaign to synthesize derivatives with an improved therapeutic index, culminating in the creation of Irofulven.[4]

Functionally, Irofulven is a DNA alkylating agent that operates through a distinctive mechanism of action. It is a prodrug that requires intracellular bioactivation by the enzyme alkenal/one oxidoreductase (AOR), also known as Prostaglandin Reductase 1 (PTGR1).[1] Upon activation, it forms highly reactive electrophiles that create unique DNA adducts, leading to the inhibition of DNA replication, S-phase cell cycle arrest, and the induction of apoptosis.[1] A key feature that distinguishes Irofulven from conventional alkylating agents is its ability to circumvent common mechanisms of drug resistance, including those mediated by p53 mutations and the overexpression of the MDR1 efflux pump.[1]