Summer Desouza
New York University
Design of Proteomimetics for the Targeted Degradation of Intrinsically Disordered Protein MYC
MYC, a transcriptional regulator of cellular growth and proliferation, is frequently dysregulated in a wide range of cancers, yet its intrinsically disordered structure and absence of well-defined binding pockets have limited the development of direct MYC-targeted therapeutics. Here, we investigate a proteomimetic strategy for the targeted degradation of MYC using cross-linked helix dimers (CHDs), which consist of two synthetically constrained helical peptides. Utilizing structural aspects of Max, the natural binding partner and activator of MYC, we previously developed a Max protein mimic, CHD-MAX, which effectively bound to and stabilized MYC. We hypothesized that these proteomimetics could be reengineered to introduce a second binding epitope specific to the E3 ubiquitin ligase MDM2. By incorporating key residues found in the MDM2-binding domain of p53 onto the CHD-MAX scaffold, we generated a bispecific proteomimetic designed to promote complexation between MYC and MDM2. The lead compound, biCHD-MAX-3, successfully binds both MYC and MDM2 with nanomolar and low-micromolar affinities, respectively, and exhibits a reduction in cellular MYC levels. Overall, this study explores the potential of this bispecific proteomimetic scaffold for the targeted degradation of previously challenging oncoproteins.
MYC, a transcriptional regulator of cellular growth and proliferation, is frequently dysregulated in a wide range of cancers, yet its intrinsically disordered structure and absence of well-defined binding pockets have limited the development of direct MYC-targeted therapeutics. Here, we investigate a proteomimetic strategy for the targeted degradation of MYC using cross-linked helix dimers (CHDs), which consist of two synthetically constrained helical peptides. Utilizing structural aspects of Max, the natural binding partner and activator of MYC, we previously developed a Max protein mimic, CHD-MAX, which effectively bound to and stabilized MYC. We hypothesized that these proteomimetics could be reengineered to introduce a second binding epitope specific to the E3 ubiquitin ligase MDM2. By incorporating key residues found in the MDM2-binding domain of p53 onto the CHD-MAX scaffold, we generated a bispecific proteomimetic designed to promote complexation between MYC and MDM2. The lead compound, biCHD-MAX-3, successfully binds both MYC and MDM2 with nanomolar and low-micromolar affinities, respectively, and exhibits a reduction in cellular MYC levels. Overall, this study explores the potential of this bispecific proteomimetic scaffold for the targeted degradation of previously challenging oncoproteins.
