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N-Arylalkyl pseudopeptide inhibitors of farnesyltransferase.

Authors
  • deSolms, S J
  • Giuliani, E A
  • Graham, S L
  • Koblan, K S
  • Kohl, N E
  • Mosser, S D
  • Oliff, A I
  • Pompliano, D L
  • Rands, E
  • Scholz, T H
  • Wiscount, C M
  • Gibbs, J B
  • Smith, R L
Type
Published Article
Journal
Journal of medicinal chemistry
Publication Date
Jul 02, 1998
Volume
41
Issue
14
Pages
2651–2656
Identifiers
PMID: 9651171
Source
Medline
License
Unknown

Abstract

Inhibitors of Ras protein farnesyltransferase are described which are reduced pseudopeptides related to the C-terminal tetrapeptide of the Ras protein that signals farnesylation. Reduction of the carbonyl groups linking the first three residues of the tetrapeptide leads to active inhibitors which are chemically unstable. Stability can be restored by alkylating the central amine of the tetrapeptide. Studies of the SAR of these alkylated pseudopeptides with concomitant modification of the side chain of the third residue led to 2(S)-(2(S)-¿[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)- methylpentyl]naphthalen-1-ylmethylamino¿acetylamino)-4 -methylsulfany lbutyric acid (11), a subnanomolar inhibitor. The methyl ester (10) of this compound exhibited submicromolar activity in the processing assay and selectively inhibited anchorage-independent growth of Rat1 cells transformed by v-ras at 2.5-5 microM.

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