Farnesyl protein transferase inhibitors targeting the catalytic zinc for enhanced binding.
Successful efforts to make farnesyl transferase (FT) inhibitors with appropriately tethered ligands designed to interact with a catalytic zinc that exist in the enzyme have been realized. Thus, by introducing either a pyridylmethylamino or propylaminolimidazole amide moieties off the 2-position of the piperidine ring, FT inhibitors with activities in the picomolar range have been achieved as exemplified by compounds 12a and 12b. An X-ray structure of 11b bound to FT shows the enhanced activity is a result of interacting with the active-site zinc.
Njoroge
F George
FG
Schering-Plough Research Institute, 2015 Galloping Hill Road, K-15-3-3545, Kenilworth, NJ 07033, USA. george.njoroge@spcorp.com
Vibulbhan
Bancha
B
Pinto
Patrick
P
Strickland
Corey
C
Kirschmeier
Paul
P
Bishop
W Robert
WR
Girijavallabhan
V
V
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020134:Catalytic Domain / Q000187:drug effects / Q000502:physiology*; D016503:Drug Delivery Systems / Q000379:methods*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D011487:Protein Conformation; D015032:Zinc / Q000378:metabolism*
D004791:Enzyme Inhibitors; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; D015032:Zinc