Use of NADPH-dependent alkenal/one oxidoreductase in the Bioactivation of Irofulven and Related Compounds that Preferentially Kill Cancer Cells

Irofulven (6-hydroxymethylacylfulvene, HMAF) is a novel anticancer chemotherapeutic that is under extensive clinical evaluation. It is an alkylating agent that is capable of forming DNA, RNA, and protein adducts that appear to be preferentially cytotoxic to human cancer cells. JHU researchers have discovered that irofulven is a prodrug that requires metabolic activation to expose its alkylating capabilities. have determined the activating enzyme to be a well known enzyme which catalyzes the reduction of the 8,9-double bond of irofulven and its progenitor illudins. This action leads to the generation of a reactive and electrophilic center about its cyclopropyl group. Researchers have shown that this enzyme is responsible for irofulven activation in a multitude of human cancers and that enzyme activity levels influence both sensitivity and resistance to this drug. Description (Set) Proposed Use (Set) Cancer is second to heart disease among the leading causes of death in the United States. Despite notable successes in the treatment of some cancers, current therapies have not yet significantly affected mortality rates for the more common cancers. Thus, new effective chemotherapeutic agents are in desperate need. Novel agents are commonly developed to target specific biomolecules that are involved in the genesis, maintenance, or spread of neoplasia or to take advantage of the unique tumor environment. With the finding that an effective anticancer compound is activated by a well known enzyme which catalyzes the reduction of the 8,9-double bond of irofulven and its progenitor illudins, a new molecular target for the design of new anticancer alkylating prodrugs and mechanism of discriminatory cancer cell killing has been identified.

Inventor(s): Dick, Ryan

Type of Offer: Licensing



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