PT  - JOURNAL ARTICLE
AU  - Evert Njomen
AU  - Theresa A. Lansdell
AU  - Allison Vanecek
AU  - Vanessa Benham
AU  - Matt P. Bernard
AU  - Ya-Ting Yang
AU  - Peter Z. Schall
AU  - Daniel Isaac
AU  - Omar Alkharabsheh
AU  - Anas Al-Janadi
AU  - Matthew B. Giletto
AU  - Edmund Ellsworth
AU  - Catherine Taylor
AU  - Terence Tang
AU  - Sarah Lau
AU  - Marc Bailie
AU  - Jamie J. Bernard
AU  - Vilma Yuzbasiyan-Gurkan
AU  - Jetze J. Tepe
TI  - Enhancing c-MYC degradation via 20S proteasome activation induces <em>in vivo</em> anti-tumor efficacy
AID  - 10.1101/2020.08.24.265470
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.08.24.265470
4099  - http://biorxiv.org/content/early/2020/08/24/2020.08.24.265470.short
4100  - http://biorxiv.org/content/early/2020/08/24/2020.08.24.265470.full
AB  - 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 molecules 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 cancer 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 targeting IDP-driven proteotoxic disorders, including cancer, and demonstrate that this new therapeutic strategy is well tolerated in vivo.Competing Interest StatementThe authors have declared no competing interest.