Selective inhibition of type-I geranylgeranyltransferase in vitro and in whole cells by CAAL peptidomimetics.
In this paper we describe the synthesis of a family of CAAL peptidomimetics as GGTase-I inhibitors. These inhibitors lack the central dipeptide AA in the key CAAL carboxy terminal sequence of geranylgeranylated proteins and are more selective for GGTase-I over FTase. In whole cells, these compounds are very potent inhibitors of the processing of the geranylgeranylated protein Rap1A without affecting the farnesylated protein H-Ras. One derivative, GGTI-298, inhibited cell division by blocking cells in the G1 phase of the cell cycle.
Qian
Y
Y
Department of Chemistry, University of Pittsburgh, PA 15260, USA.
Vogt
A
A
Vasudevan
A
A
Sebti
S M
SM
Hamilton
A D
AD
D016475:3T3 Cells / Q000187:drug effects / Q000201:enzymology; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D051379:Mice; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D017368:Protein Prenylation; D013329:Structure-Activity Relationship; D020668:rap GTP-Binding Proteins
D004791:Enzyme Inhibitors; D009842:Oligopeptides; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D019204:GTP-Binding Proteins; D020668:rap GTP-Binding Proteins