Aberrant receptor tyrosine kinase (RTK) signaling is a major underlying cause of various developmental disorders and hyperproliferative diseases (Blume-Jensen et al., “Oncogenic kinase signalling”. Nature 2001, 411, 355). A primary transduction mechanism by which RTK signals are propagated to intracellular pathways involves the ligand-dependent activation of the small guanine nucleotide binding protein Ras (FIG. 1) (Buday et al., “Many faces of Ras activation.” Biochim. Biophys. Acta 2008, 1786, 178). Accordingly, design of Ras signaling pathway inhibitors has been an active area of research for anticancer therapy (Downward et al., “Targeting Ras signalling pathways in cancer therapy.” Nat. Rev. Cancer 2003, 3, 11). The rate-limiting step in Ras activation process is the conversion of Ras-GDP to Ras-GTP through an exchange reaction that is catalyzed by the Ras specific guanine nucleotide exchange factor Sos (FIG. 2). The highly conserved catalytic domain (Rem+cdc25) of Sos interacts with Ras at a helical hairpin composed of the α-H and α-I helices (FIG. 3). The helical hairpin may be capable of nucleotide dissociation from Ras and subsequent down-regulation of the Ras pathway (Sacco et al., “The isolated catalytic hairpin of the Ras-specific guanine nucleotide exchange factor Cdc25(Mm) retains nucleotide dissociation activity but has impaired nucleotide exchange activity.” Febs Lett. 2005, 579, 6851). The high resolution structures of this complex suggest that the α-H helix is the only portion of the helical hairpin that makes direct contact with Ras, while the α-I helix may only serve to stabilize the α-H conformation (Boriack-Sjodin, et al. “The structural basis of the activation of Ras by Sos.” Nature 1998, 394, 337).
Inhibitors of the Ras-Sos interactions would be valuable as tools to dissect this complex signaling pathway and as leads for anticancer drug design. However, despite the availability of a high resolution crystal structure of the Ras/Sos complex since 1998, direct inhibitors of this complex have not been reported. Therefore, there remains a need for methods and compositions for treating developmental disorders and hyperproliferative diseases by inhibiting undesirable activities associated with Ras proteins, for example by inhibition of the Ras/Sos complex. The invention addresses these and other needs.