Synthesis and evaluation of hydroxyproline-derived isoprenyltransferase inhibitors.
A series of peptidomimetics based on a hydroxyproline scaffold was prepared and evaluated for inhibition of farnesyltransferase and geranylgeranyltransferase I in both enzymatic and cell-based assays. A number of analogs were potent and selective inhibitors of FTase, while one compound (22) was nonselective in the enzymatic assays but eight-fold selective for inhibition of GGTase in the cellular assay (IC50 = 0.39 microM).
O'Connell
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CE
Eisai Research Institute, Andover, MA 01810, USA.
Ackermann
K
K
Rowell
C A
CA
Garcia
A M
AM
Lewis
M D
MD
Schwartz
C E
CE
D016475:3T3 Cells / Q000187:drug effects; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006909:Hydroxyproline / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D018716:Molecular Mimicry; D010455:Peptides / Q000737:chemistry*; D013329:Structure-Activity Relationship
C096694:B 956; D004791:Enzyme Inhibitors; D010455:Peptides; D008715:Methionine; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; C064911:p21(ras) farnesyl-protein transferase; D006909:Hydroxyproline