Development of highly potent inhibitors of Ras farnesyltransferase possessing cellular and in vivo activity.

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 microM. 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 microM, 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.

• Authors: K Leftheris, T Kline, G D Vite, Y H Cho, R S Bhide, D V Patel, M M Patel, R J Schmidt, H N Weller, M L Andahazy, J M Carboni, J L Gullo-Brown, F Y Lee, C Ricca, W C Rose, N Yan, M Barbacid, J T Hunt, C A Meyers, B R Seizinger, R Zahler, V Manne
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 39 Issue 1 Pg. 224-36 (Jan 05 1996) ISSN: 0022-2623 [Print] United States
• PMID: 8568812 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Glutamates
• Isoquinolines
• N-((2-(N-(2-amino-3-mercaptopropyl)-3-methylvalyl)-1,2,3,4-tetrahydro-3-isoquinolinyl)carbonyl)glutamine
• Tetrahydroisoquinolines
• methyl N-((2-(N-(2-amino-3-mercaptopropyl)-3-methylvalyl)-1,2,3,4-tetrahydro-3-isoquinolinyl)carbonyl)methionine
• Methionine
• Transferases
• Alkyl and Aryl Transferases
• geranylgeranyltransferase type-I
• p21(ras) farnesyl-protein transferase
• Oncogene Protein p21(ras)
• Valine

Topics

• 3T3 Cells
• Alkyl and Aryl Transferases
• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Brain (enzymology)
• Cell Division (drug effects)
• Cell Line, Transformed
• Cell Transformation, Neoplastic (drug effects)
• Drug Design
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Genes, ras (genetics)
• Glutamates (chemical synthesis, chemistry, pharmacology)
• Isoquinolines (chemical synthesis, chemistry, pharmacology)
• Methionine (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Mice
• Mice, Nude
• Molecular Structure
• Neoplasm Transplantation
• Oncogene Protein p21(ras) (metabolism)
• Protein Prenylation (drug effects)
• Rats
• Swine
• Tetrahydroisoquinolines
• Transfection
• Transferases (antagonists & inhibitors)
• Tumor Cells, Cultured
• Valine (analogs & derivatives, chemical synthesis, chemistry, pharmacology)