Development of Highly Potent Inhibitors of Ras Farnesyltransferase Possessing Cellular andin VivoActivity

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Abstract
Analogs of CVFM (a known nonsubstrate farnesyltransferase (FT) inhibitor derived from a CA1A2X sequence where C is cysteine, A is an aliphatic residue, and X is any residue) were prepared where phenylalanine was replaced by (Z)-dehydrophenylalanine, 2-aminoindan-2-carboxylate, 1,2,3,4-tetrahydroisoquinoline-3-carboxylate (Tic), and indoline-2-carboxylate. The greatest improvement in FT inhibitory potency was observed for the Tic derivative (IC50 = 1 nM); however, this compound was ineffective in blocking oncogenic Ras-induced transformation of NIH-3T3 fibroblast cells. A compound was prepared in which both the Cys-Val methyleneamine isostere and the Tic replacement were incorporated. This derivative inhibited FT with an IC50 of 0.6 nM and inhibited anchorage-independent growth of stably transformed NIH-3T3 fibroblast cells by 50% at 5 μM. Replacing the A1 side chain of this derivative with a tert-butyl group and replacing the X position with glutamine led to a derivative with an IC50 of 2.8 nM and an EC50 of 0.19 μM, a 26-fold improvement over (S*,R*)-N-[[2-[N-(2-amino-3-mercaptopropyl)-l-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-l-methionine. This derivative, (S*,R*)-N-[[2-[N-(2-amino-3-mercaptopropyl)-l-tert-leucyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-l-glutamine, was evaluated in vivo along with (S*,R*)-N-[[2-[N-(2-amino-3-mercaptopropyl)-l-tert-leucyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-l-methionine methyl ester for antitumor activity in an athymic mouse model implanted ip with H-ras-transformed rat-1 tumor cells. When administered by injection twice a day at 45 mg/kg for 11 consecutive days, both compounds showed prolonged survival time (T/C = 142−145%), thus demonstrating efficacy against ras oncogene-containing tumors in vivo.