Inhibitors of RAS signal transduction as antitumor agents

Anarchic cell proliferation, observed in some leukemia and in breast and ov arian cancers, has been related to dysfunctioning of cytoplasmic or recepto r 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 activ ation of Ras. This review shows how it is possible to stop the Ras-deregula ted signaling pathway to obtain potential antitumor agents. Grb2 protein is comprised of one SH2 surrounded by two SH3 domains and interacts by means uf its Src homology (SH2) domain with phosphotyrosine residues of target pr oteins such as the epidermal growth factor (EGF) receptor or the Shc adapto r. By means of its SH3 domains, Grb2 recognizes proline-rich sequences of S os, leading to Ras activation, inhibitors of SH2 and SH3 domains were desig ned with the aim of interrupting Grb2 recognition. On the one hand, using s tructural data and molecular modeling, peptide dimers or "peptidimers", mad e 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 co mplexed with a phosphotyrosine (pTyr)-containing peptide and molecular mode ling studies, a series of N-protected tripeptides containing two phosphotyr osine or mimetic residues, with one pTyr sterically constrained, were devis ed. These compounds show very high affinities for Grb2 in vitro. They have been targeted into cells showing selective antiproliferative activity on tu mor cells. These results suggest that inhibiting SH2 or SH3 domains of sign aling proteins might provide antitumor agents. BIOCHEM PHARMACOL 60;8:1165- 1169, 2000. (C) 2000 Elsevier Science Inc.