3TIK: Sterol 14-alpha Demethylase (Cyp51) From Trypanosoma Brucei in Complex With the Tipifarnib Derivative 6-((4-chlorophenyl)(methoxy)(1-methyl- 1h-imidazol-5-yl)methyl)-4-(2,6-difluorophenyl)-1-methylquinolin- 2(1h)-one

Chagas disease, caused by the protozoan pathogen Trypanosoma cruzi, remains a challenging infection due to the unavailability of safe and efficacious drugs. Inhibitors of the trypanosome sterol 14alpha-demethylase enzyme (CYP51), including azole antifungal drugs, are promising candidates for development as anti-Chagas disease drugs. Posaconazole is under clinical investigation for Chagas disease, although the high cost of this drug may limit its widespread use. We have previously reported that the human protein farnesyltransferase (PFT) inhibitor tipifarnib has potent anti-T. cruzi activity by inhibiting the CYP51 enzyme. Furthermore, we have developed analogs that minimize the PFT-inhibitory activity and enhance the CYP51 inhibition. In this paper, we describe the efficacy of the lead tipifarnib analog compared to that of posaconazole in a murine model of T. cruzi infection. The plasma exposure profiles for each compound following a single oral dose in mice and estimated exposure parameters after repeated twice-daily dosing for 20 days are also presented. The lead tipifarnib analog had potent suppressive activity on parasitemia in mice but was unsuccessful at curing mice, whereas posaconazole as well as benznidazole cured 3 of 5 and 4 of 6 mice, respectively. The efficacy results are consistent with posaconazole having substantially higher predicted exposure than that of the tipifarnib analog after repeat twice-daily administration. Further changes to the tipifarnib analogs to reduce plasma clearance are therefore likely to be important. A crystal structure of a trypanosomal CYP51 bound to a tipifarnib analog is reported here and provides new insights to guide structure-based drug design for further optimized compounds.
PDB ID: 3TIKDownload
MMDB ID: 101119
PDB Deposition Date: 2011/8/20
Updated in MMDB: 2012/09 
Experimental Method:
x-ray diffraction
Resolution: 2.05  Å
Source Organism:
Similar Structures:
Biological Unit for 3TIK: tetrameric; determined by author
Molecular Components in 3TIK
Label Count Molecule
Proteins (4 molecules)
Sterol 14-alpha Demethylase (Cyp51)
Molecule annotation
Chemicals (8 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB