SELECTIVE-INHIBITION OF TYPE-I GERANYLGERANYLTRANSFERASE IN-VITRO ANDIN WHOLE CELLS BY CAAL PEPTIDOMIMETICS

In this paper we describe the synthesis of a family of CAAL peptidomim etics as GGTase-I inhibitors. These inhibitors lack the central dipept ide AA in the key CAAL carboxy terminal sequence of geranylgeranylated proteins and are more selective for GGTase-I over FTase. In whole cel ls, these compounds are very potent inhibitors of the processing of th e geranylgeranylated protein Rap1A without affecting the farnesylated protein H-Ras. One derivative, GGTI-298, inhibited cell division by bl ocking cells in the G(1) phase of the cell cycle. (C) 1998 Elsevier Sc ience Ltd. All rights reserved.