Guiding farnesyltransferase inhibitors from an ECLiPS library to the catalytic zinc

Chia-Yu Huang; Tara M Stauffer; Corey L Strickland; John C Reader; He Huang; Ge Li; Alan B Cooper; Ronald J Doll; Ashit K Ganguly; John J Baldwin; Laura L Rokosz

doi:10.1016/j.bmcl.2005.10.070

Guiding farnesyltransferase inhibitors from an ECLiPS library to the catalytic zinc

Bioorg Med Chem Lett. 2006 Feb;16(3):507-11. doi: 10.1016/j.bmcl.2005.10.070. Epub 2005 Nov 10.

Authors

Chia-Yu Huang¹, Tara M Stauffer, Corey L Strickland, John C Reader, He Huang, Ge Li, Alan B Cooper, Ronald J Doll, Ashit K Ganguly, John J Baldwin, Laura L Rokosz

Affiliation

¹ Pharmacopeia Drug Discovery, PO Box 5350, Princeton, NJ 08543-5350, USA.

PMID: 16289818
DOI: 10.1016/j.bmcl.2005.10.070

Abstract

Farnesyltransferase inhibitors identified from an ECLiPS library were optimized using solution-phase synthesis. X-ray crystallography of inhibited complexes was used to identify substructures that coordinate to the active site zinc. The X-ray structures were ultimately used to guide the design of second-generation analogs with FTase IC(50)s of less than 1.0 nM.

MeSH terms

Animals
Binding Sites
Catalysis
Crystallography, X-Ray
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / pharmacology*
Farnesyltranstransferase / antagonists & inhibitors*
Farnesyltranstransferase / chemical synthesis
Inhibitory Concentration 50
Mice
NIH 3T3 Cells
Peptide Library*
Structure-Activity Relationship
Zinc / chemistry*

Substances

Enzyme Inhibitors
Peptide Library
Farnesyltranstransferase
Zinc