FARNESYL DERIVATIVES OF RIGID CARBOXYLIC ACIDS-INHIBITORS OF RAS-DEPENDENT CELL-GROWTH

Inhibitors of the enzyme that methylates ras proteins, the prenylated protein methyltransferase (PPMTase), are described. They are farnesyl derivatives of rigid carboxylic acids that recognize the farnesylcyste ine recognition domain of the enzyme but do not serve as substrates. T hey also inhibit ras-dependent cell growth by a mechanism that is prob ably unrelated to inhibition of ras methylation, even though their pot encies as PPMTase inhibitors and cell-growth inhibitors correlate well . The most potent inhibitor is S-trans,trans-farnesylthiosalicylic aci d (FTS) (2). FTS (2) selectively inhibits the growth of human Ha-ras-t ransformed Rat1 cells in vitro (EC(50) = 7.5 mu M).