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Inhibitors of Ras signal transduction as antitumor agents
1Département de Pharmacochimie Moléculaire et Structurale, U266 INSERM, UMR 8600 CNRS, UFR des Sciences Pharmaceutiques et Biologiques, 75270 Paris Cedex 06, France. Garbay@pharmacie.univ-paris5.fr
Abstract:
Anarchic cell proliferation, observed in some leukemia and in breast and ovarian cancers, has been related to dysfunctioning of cytoplasmic or receptor tyrosine kinase activities coupled to p21 Ras. The growth factor receptor-bound protein 2 (Grb2) adaptor when complexed with Sos (Son of sevenless), the exchange factor of Ras, conveys the signal induced by tyrosine kinase-activated receptor to Ras by recruiting Sos to the membrane, allowing activation of Ras. This review shows how it is possible to stop the Ras-deregulated signaling pathway to obtain potential antitumor agents. Grb2 protein is comprised of one SH2 surrounded by two SH3 domains and interacts by means of its Src homology (SH2) domain with phosphotyrosine residues of target proteins such as the epidermal growth factor (EGF) receptor or the Shc adaptor. By means of its SH3 domains, Grb2 recognizes proline-rich sequences of Sos, leading to Ras activation. Inhibitors of SH2 and SH3 domains were designed with the aim of interrupting Grb2 recognition. On the one hand, using structural data and molecular modeling, peptide dimers or "peptidimers", made up of two proline-rich sequences from Sos linked by an optimized spacer, were developed. On the other, using the structure of the Grb2 SH2 domain complexed with a phosphotyrosine (pTyr)-containing peptide and molecular modeling studies, a series of N-protected tripeptides containing two phosphotyrosine or mimetic residues, with one pTyr sterically constrained, were devised. These compounds show very high affinities for Grb2 in vitro. They have been targeted into cells showing selective antiproliferative activity on tumor cells. These results suggest that inhibiting SH2 or SH3 domains of signaling proteins might provide antitumor agents.
Insights
Targeting the Grb2 protein
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Anarchic cell proliferation in cancers like leukemia, breast, and ovarian cancers is linked to dysregulated tyrosine kinase and Ras signaling.
- The Grb2 (growth factor receptor-bound protein 2) adaptor protein, complexed with Sos (Son of sevenless), is crucial for transmitting signals from activated receptors to Ras, promoting cell growth.
Purpose of the Study:
- To explore strategies for inhibiting the Ras-deregulated signaling pathway to develop potential antitumor agents.
- To investigate the inhibition of Grb2 protein interactions as a therapeutic approach.
Main Methods:
- Design and development of "peptidimers" using structural data and molecular modeling, consisting of two proline-rich sequences from Sos linked by a spacer.
- Creation of N-protected tripeptides with phosphotyrosine or mimetic residues, incorporating steric constraints, based on Grb2 SH2 domain structure and molecular modeling.
- In vitro affinity assays and cell-based assays to evaluate compound efficacy.
Main Results:
- Developed peptidimers and phosphotyrosine-containing tripeptides with high affinity for Grb2 in vitro.
- Demonstrated selective antiproliferative activity of these compounds against tumor cells.
- Indicated that inhibiting Grb2's SH2 or SH3 domains can disrupt oncogenic signaling.
Conclusions:
- Inhibiting the Grb2 protein's SH2 and SH3 domains offers a promising strategy for developing novel antitumor agents.
- Targeting specific protein-protein interactions within the Ras signaling pathway can lead to effective cancer therapies.