Development of Grb2 SH2 Domain Signaling Antagonists: A Potential New Class of Antiproliferative Agents

Abstract

Aberrant signaling through protein-tyrosine kinase (PTK)-dependent pathways is associated with several proliferative diseases. Accordingly, PTK inhibitors are being developed as new approaches for the treatment of certain cancers. Growth factor receptor bound protein 2 (Grb2) is an important downstream mediator of PTK signaling that serves obligatory roles in many pathogenic processes. One of the primary functions of Grb2 is to bind to specific phosphotyrosyl (pTyr)-containing sequences through its Src homology 2 (SH2) domain. Agents that bind to the Grb2 SH2 domain and prevent its normal function could disrupt associated PTK signaling and serve as alternatives to kinase-directed inhibitors. Starting from the X-ray crystal structure of a lead peptide bound to the Grb2 SH2 domain, this review will summarize important contributions to these efforts. The presentation will be thematically arranged according to the region of peptide modified, proceeding from the N-terminus to the C-terminus, with a special section devoted to aspects of conformational constraint.

Fig. 1.

X-ray crystal structure of the BCR-Abl_174–180 sequence KPFpYVNV complexed to the Grb2 SH2 domain as reported in (Rahuel et al., 1996) with N-terminal Lys and Pro residues having been omitted for clarity. Important protein residues discussed in the text have been rendered in CPK style and labeled.

Fig. 2.

Amino-terminal modifications reported in (Furet et al., 1997).

Fig. 3.

Amino-terminal modifications presented in (Burke et al., 2001a).

Fig. 4.

Structures of various di-acidic pTyr mimetics.

Fig. 5.

Structures of various mono-acidic pTyr mimetics.

Fig. 6.

Systematic modifications to the pTyr+1 residue as reported in (Garcia-Echeverria et al., 1999).

Fig. 7.

Examination of bend-inducing pTyr mimetics at the i+1 position as reported in (Liu et al., 1999).

Fig. 8.

Replacement of the pTyr+2 Asn residue as reported in (Furet et al., 1999).

Fig. 9.

Modifications to the C-terminal pTyr+3 position.

Fig. 10.

Structures of conformationally-constrained monomeric pTyr mimetics.

Fig. 11.

Constrained pTyr mimetics within peptide platforms.

Fig. 12.

Structures of cyclic peptides reported in (Ettmayer et al., 1999).

Fig. 13.

RCM-derived peptides described in (Dekker et al., 2003).

Fig. 14.

Structures of Grb2 SH2 domain-binding cyclic peptides based on the non-pTyr-containing phage library-derived lead 19a. Grey indicates phenyl phosphoryl-mimicking functionality.

Fig. 15.

Macrocycles formed by RCM reactions originating at the pTyr mimetic β-position.

Fig. 16.

RCM macrocyclization at the pTyr mimetic β-position using C-terminal allylglycine residues.

Fig. 17.

Non-peptidic compounds 38 and 39 based on tripeptide 38.

Fig. 18.

Structures of Grb2 SH2 domain-binding inhibitors that have been examined in whole cell systems.