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Inhibitors of farnesyltransferase and Ras processing peptidase
C C Hall1, J D Watkins, S B Ferguson
1Department of Oncology, Hoffmann-La Roche Inc., Nutley, NJ 07110-1199, USA.
Abstract:
Four analogs of the carboxy terminus of unprocessed p21Ras protein were evaluated as inhibitors of the p21Ras processing farnesyltransferase and peptidase. While three showed no crossover of inhibitory activity between the enzymes, the fourth (a naphthyl-substituted peptide) inhibited both farnesyltransferase and peptidase, with IC50s of 16 microM and 3 microM, respectively. Such inhibition of more than one step of Ras processing may complicate assessment of the mode of action for some inhibitors of Ras processing peptidase.
Insights
Researchers explored analogs of the p21Ras protein terminus as inhibitors. One naphthyl-substituted peptide analog inhibited both farnesyltransferase and peptidase enzymes involved in Ras processing.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- The p21Ras protein is crucial in cellular signaling pathways.
- Proper processing of p21Ras involves farnesyltransferase and peptidase enzymes.
- Inhibiting these enzymes is a target for cancer therapeutics.
Purpose of the Study:
- To evaluate carboxy-terminal analogs of p21Ras as inhibitors of its processing enzymes.
- To identify inhibitors with dual activity against farnesyltransferase and peptidase.
- To understand the implications of dual inhibition on assessing inhibitor mechanisms.
Main Methods:
- Synthesis of four carboxy-terminal analogs of p21Ras.
- Enzyme inhibition assays for farnesyltransferase and peptidase.
- Determination of IC50 values for active compounds.
Main Results:
- Three analogs exhibited specific inhibitory activity against either farnesyltransferase or peptidase.
- One naphthyl-substituted peptide analog demonstrated dual inhibitory activity.
- The dual inhibitor showed IC50 values of 16 microM for farnesyltransferase and 3 microM for peptidase.
Conclusions:
- A novel naphthyl-substituted peptide analog inhibits both p21Ras farnesyltransferase and peptidase.
- Dual inhibition of Ras processing steps can complicate the determination of inhibitor mechanisms.
- This finding has implications for the development of Ras-targeted therapies.