First-in-class heterobifunctional proteomimetic polymer capable of direct inhibition of Myc and target it for degradation

Background: The proto-oncogene Myc is known to play critical roles in tumorigenesis and therapeutic resistance, being dysregulated up 70% of all human cancers. Heterodimerization with its binding partner Max required for oncogenic transformation, yet the development small molecule inhibitors has been hampered due lack suitable pockets. inhibitory peptides derived from first helix (H1) bHLH-LZ region have developed efforts address this limitation. However, poor pharmacokinetic profiles precluded clinical translation these approaches. Here, we use a novel platform technology referred as Protein-Like Polymer (PLP) more potent inhibitors. Material Methods: PLPs were generated using ring-opening metathesis polymerization (ROMP) wherein occupy every side chain, resulting structures highly resistant proteolysis. Characterization was done HPLC, LC-MS, NMR, GPC. Toxicity screening performed both neoplastic benign cell lines. Taking advantage ability multiplex different payloads sequence-controlled manner, heterofunctional designed by incorporating secondary sequences imbuing desirable functionalities. Two specific explored: M1 nuclear localization sequence (NLS) degron (RRRG) engage endogenous cellular machinery targeted protein degradation. Fluorescently labeled used quantify uptake confocal microscopy FACs. Biophysical analysis confirm target engagement Results: A library narrow polydispersity predetermined degrees generated. Cell assays revealed formulation-dependent antiproliferative effects submicromolar IC50 values Myc-dependent manner. High levels observed across formulations, NLS containing showing slightly elevated accumulation. EBox (Myc transcription site) luciferase reporter assay showed decreased signal only Myc-targeted PLP treatments, suggesting Myc-specific effects. Western blotting minor reductions H1-PLP H1-NLS-PLP treatment groups, but significant decreases level H1-degron-PLPs. RNAseq selective overexpression pathway genes. Mice bearing transplanted Myc-CaP tumors delayed tumor growth following Myc-degrading ongoing. Conclusion: We present peptide delivery that addresses challenges inherent presented work demonstrates feasibility delivering provides rationale further vivo studies models. No conflict interest.