Synthesis and biological activity of ras farnesyl protein transferase inhibitors. Tetrapeptide analogs with amino methyl and carbon linkages.
Replacement of the central amino methylene linkage of C[psi CH2NH]A[psi CH2NH]AX tetrapeptide inhibitors with carbon tethers led to compounds with potency in the nanomolar range. Some of the more potent olefinic compounds inhibit Ras processing in intact v-ras transformed NIH 3T3 cells with IC50 values in the 0.1 to 1 microM range, and inhibit selectively the anchorage-independent growth of H-ras transformed Rat1 cells at 10 microM.
Wai
J S
JS
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486.
Bamberger
D L
DL
Fisher
T E
TE
Graham
S L
SL
Smith
R L
RL
Gibbs
J B
JB
Mosser
S D
SD
Oliff
A I
AI
Pompliano
D L
DL
Rands
E
E
D016475:3T3 Cells; D019883:Alkyl and Aryl Transferases; D000595:Amino Acid Sequence; D000818:Animals; D002472:Cell Transformation, Viral; D011905:Genes, ras; D051379:Mice; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014166:Transferases / Q000037:antagonists & inhibitors*
D009842:Oligopeptides; D014166:Transferases; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase