title: Rational modification of a candidate cancer drug for use against Chagas disease.
abstract: Chagas disease is one of the major neglected diseases of the world. Existing drug therapies are limited, ineffective, and highly toxic. We describe a novel strategy of drug discovery of adapting an existing clinical compound with excellent pharmaceutical properties to target a pathogenic organism. The protein farnesyltransferase (PFT) inhibitor tipifarnib, now in phase III anticancer clinical trials, was previously found to kill Trypanosoma cruzi by blocking sterol 14 alpha-demethylase (14DM). We rationally developed tipifarnib analogues that display reduced affinity for human PFT to reduce toxicity while increasing affinity for parasite 14DM. The lead compound has picomolar activity against cultured T. cruzi and is efficacious in a mouse model of acute Chagas disease.
authors.affiliation: Department of Chemistry, University of Washington, Seattle, Washington 98195-7185, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Kraus
authors.forename: Christophe L M J
authors.initials: CL
authors.lastname: Verlinde
authors.forename: Mandana
authors.initials: M
authors.lastname: Karimi
authors.forename: Galina I
authors.initials: GI
authors.lastname: Lepesheva
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gelb
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Buckner
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D014355:Chagas Disease / Q000188:drug therapy*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D015363:Quinolones; D014344:Trypanocidal Agents; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; C402769:tipifarnib