Enhancing c-MYC degradation via 20S proteasome activation inducesin vivoanti-tumor efficacy

Abstract

Enhancing proteasome activity is a potential new therapeutic strategy to prevent the accumulation of aberrant high levels of protein that drive the pathogenesis of many diseases. Herein, we examine the use of small mole-cules to activate the 20S proteasome to reduce aberrant signaling by the undruggable oncoprotein c-MYC, to treat c-MYC driven oncogenesis. Overexpression of c-MYC is found in more than 50% of all human cancer but remains undruggable because of its highly dynamic intrinsically disordered 3-D conformation, which renders traditional therapeutic strategies largely ineffective. We demonstrate herein that small molecule activation of the 20S proteasome targets dysregulated intrinsically disordered proteins (IDPs), including c-MYC, and reduces can-cer growth in vitro and in vivo models of multiple myeloma, and is even effective in bortezomib resistant cells and unresponsive patient samples. Genomic analysis of various cancer pathways showed that proteasome activation results in downregulation of many c-MYC target genes. Moreover, proteasome enhancement was well tolerated in mice and dogs. These data support the therapeutic potential of 20S proteasome activation in tar-geting IDP-driven proteotoxic disorders, including cancer, and demonstrate that this new therapeutic strategy is well tolerated in vivo.

Advances in Proteasome Enhancement by Small Molecules

“…These soluble oligomeric forms are also responsible for impairing proteasome function, which further drives disease progression [ 94 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 ]. Multiple studies have indicated that enhancing proteasome proteolytic activity prevents the accumulation of these IDPs, reduces brain damage and improves cognitive performance in mouse models, and may be a new therapeutic strategy to treat neurodegenerative diseases [ 8 , 68 , 69 , 70 , 72 , 119 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 ]. More recently, it has been recognized that the 20S proteasome of the proteasome plays a critical role in maintaining proteostasis by the direct degradation of oxidatively damaged and highly disordered proteins [ 10 , 133 , 134 , 135 , 136 , 137 , 138 ].…”

Substituted Imidazoline Synthesis: A Diastereo- and Enantioselective aza-Henry Route to a Human Proteasome Modulator

“…Tepe and co-workers discovered that trans -imidazolines such as 1 (Scheme A) specifically bind to the human proteasome in a noncompetitive fashion. − Aside from overcoming acquired resistance to active-site inhibitors, this type of modulation may curb toxicity by limiting off-target effects. Importantly, these imidazolines inhibit general NF-κB mediated transcription in cell culture and cytokine production in stimulated human blood, and appear noncytotoxic at concentrations up to 10 μM .…”