Guiding farnesyltransferase inhibitors from an ECLiPS library to the catalytic zinc.
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.
Huang
Chia-Yu
CY
Pharmacopeia Drug Discovery, PO Box 5350, Princeton, NJ 08543-5350, USA.
Stauffer
Tara M
TM
Strickland
Corey L
CL
Reader
John C
JC
Huang
He
H
Li
Ge
G
Cooper
Alan B
AB
Doll
Ronald J
RJ
Ganguly
Ashit K
AK
Baldwin
John J
JJ
Rokosz
Laura L
LL
D000818:Animals; D001665:Binding Sites; D002384:Catalysis; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis; D020128:Inhibitory Concentration 50; D051379:Mice; D041681:NIH 3T3 Cells; D019151:Peptide Library; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry*
D004791:Enzyme Inhibitors; D019151:Peptide Library; D051231:Farnesyltranstransferase; D015032:Zinc