| We describe the design, synthesis and biochemical evaluation of molecules that recognize exterior protein surfaces and effectively modulate clinically important protein-protein and protein-DNA interactions.;In the second chapter, several organic scaffolds that effectively target the FBP-FUSE protein-DNA interaction are presented. Deregulated or elevated expression of c-myc has been implicated in a wide array of human carcinomas, and disruption of far-upstream element (FUSE) binding protein (FBP) function may lead to the inhibition of c-myc driven tumors. FBP regulates c-myc expression through its interaction with single-stranded DNA known as the FUSE, which is located upstream of the c-myc promoter. Inhibitors based on a previously reported lead ligand display micromolar affinity in vitro and predominantly target the DNA binding domain of FBP, as determined by HSQC NMR experiments. Alternative strategies, including porphyrins and beta-peptide based DNA mimetics were also explored and provided insight into the critical binding interactions between FBP and its DNA partner.;In the third chapter, small molecule alpha-helix mimetics that disrupt the intramolecular protein-protein interaction between the Rho GEF Tim and its N-terminal auto-inhibitory helix are reported. Tim is responsible for the activation of Rho GTPases, which have been shown to play a role in tumorigenesis. It is believed that Tim is auto-inhibited by its N-terminal helix that excludes the binding of Rho GTPases and prevents their activation. This auto-inhibition is relieved by phosphorylation, truncation or mutation of the helix. Compounds that mimic the critical binding residues found at the i, i + 1 and i + 4 positions of the Tim auto-inhibitory helix have been designed as a strategy to inhibit aberrant Tim exchange activity and constitutive activation of Rho GTPases. Helix mimetics based on a 1,3,5-trisubstituted phenyl scaffold and a phenylpyridone scaffold show significant decrease in Tim exchange activity, with the lowest IC50 values reported to date for this interaction. These compounds represent promising leads that will be further optimized in an effort to increase potency.;In the final chapter, the development of a new foldamer that mimics an extended beta-sheet is described. The non-peptidic mimetic is based on a series of 2,2-disubstituted-indolin-3-one groups linked through their 4,7 positions by an alkyne spacer. An intramolecular hydrogen bond between the carbonyl of one indolinone subunit and the proximal NH of another subunit imposes a conformation that mimics the side chain positioning on a beta-strand. X-ray crystallographic studies support the presence of this intramolecular hydrogen bond. The described approach allows extension of the scaffold to longer oligomers that will form the basis of new mimetics for the disruption of therapeutically relevant protein-protein interactions that rely on the contacts of side chain residues on two beta-strands. |
