Rational modification of a candidate cancer drug for use against Chagas disease.

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Kraus JM, Verlinde CL, Karimi M, Lepesheva GI, Gelb MH, Buckner FS

Rational modification of a candidate cancer drug for use against Chagas disease.

J Med Chem. 2009 Mar 26;52(6):1639-47. doi: 10.1021/jm801313t.

PubMed ID

19239254 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Posaconazole	Cytochrome P450 3A4	IC 50 (nM)	350	N/A	N/A	Details