title: 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.affiliation: Department of Oncology Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
authors.forename: K
authors.initials: K
authors.lastname: Leftheris
authors.forename: T
authors.initials: T
authors.lastname: Kline
authors.forename: G D
authors.initials: GD
authors.lastname: Vite
authors.forename: Y H
authors.initials: YH
authors.lastname: Cho
authors.forename: R S
authors.initials: RS
authors.lastname: Bhide
authors.forename: D V
authors.initials: DV
authors.lastname: Patel
authors.forename: M M
authors.initials: MM
authors.lastname: Patel
authors.forename: R J
authors.initials: RJ
authors.lastname: Schmidt
authors.forename: H N
authors.initials: HN
authors.lastname: Weller
authors.forename: M L
authors.initials: ML
authors.lastname: Andahazy
authors.forename: J M
authors.initials: JM
authors.lastname: Carboni
authors.forename: J L
authors.initials: JL
authors.lastname: Gullo-Brown
authors.forename: F Y
authors.initials: FY
authors.lastname: Lee
authors.forename: C
authors.initials: C
authors.lastname: Ricca
authors.forename: W C
authors.initials: WC
authors.lastname: Rose
authors.forename: N
authors.initials: N
authors.lastname: Yan
authors.forename: M
authors.initials: M
authors.lastname: Barbacid
authors.forename: J T
authors.initials: JT
authors.lastname: Hunt
authors.forename: C A
authors.initials: CA
authors.lastname: Meyers
authors.forename: B R
authors.initials: BR
authors.lastname: Seizinger
authors.forename: R
authors.initials: R
authors.lastname: Zahler
authors.forename: V
authors.initials: V
authors.lastname: Manne
mesh_terms: D016475:3T3 Cells; D019883:Alkyl and Aryl Transferases; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001921:Brain / Q000201:enzymology; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011905:Genes, ras / Q000235:genetics; D005971:Glutamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008715:Methionine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D015689:Oncogene Protein p21(ras) / Q000378:metabolism*; D017368:Protein Prenylation / Q000187:drug effects; D051381:Rats; D013552:Swine; D044005:Tetrahydroisoquinolines; D014162:Transfection; D014166:Transferases / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D014633:Valine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005971:Glutamates; D007546:Isoquinolines; C097777:N-((2-(N-(2-amino-3-mercaptopropyl)-3-methylvalyl)-1,2,3,4-tetrahydro-3-isoquinolinyl)carbonyl)glutamine; D044005:Tetrahydroisoquinolines; C097778:methyl N-((2-(N-(2-amino-3-mercaptopropyl)-3-methylvalyl)-1,2,3,4-tetrahydro-3-isoquinolinyl)carbonyl)methionine; D008715:Methionine; D014166:Transferases; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; C064911:p21(ras) farnesyl-protein transferase; D015689:Oncogene Protein p21(ras); D014633:Valine