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Small Molecule 20S Proteasome Enhancer Regulates MYC Protein Stability and Exhibits Antitumor Activity in Multiple

Evert Njomen1,2, Allison Vanecek1, Theresa A Lansdell2

  • 1Department of Chemistry, Michigan State University, East Lansing, MI 48824, USA.

Biomedicines
|May 28, 2022
PubMed

Insights

A novel small molecule, TCH-165, activates the 20S proteasome to reduce MYC protein levels. This approach shows therapeutic potential for treating multiple myeloma (MM) and other MYC-driven cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Multiple myeloma (MM) remains a significant challenge, with refractory and relapsing cases limiting overall survival despite new treatments.
  • The oncogenic transcription factor MYC is overexpressed in over 70% of human cancers, including MM, driving tumor development.
  • MYC protein levels are regulated by proteasomal degradation, including both ubiquitin-dependent (26S proteasome) and ubiquitin-independent (20S proteasome via REGγ) pathways.

Purpose of the Study:

  • To investigate the therapeutic potential of activating the 20S proteasome using a small molecule activator, TCH-165, for treating multiple myeloma.
  • To determine if TCH-165 can decrease MYC protein levels and impact cancer cell growth in MM models.

Main Methods:

  • Utilized a small molecule activator of the 20S proteasome, TCH-165.
  • Assessed MYC protein levels and degradation pathways in in vitro and in vivo models of multiple myeloma.
  • Analyzed apoptotic signaling through targeted gene expression analysis of cancer pathways.
  • Evaluated the tolerability of 20S proteasome enhancement in mouse and dog models.

Main Results:

  • TCH-165 was demonstrated to decrease MYC protein levels, mimicking REGγ-mediated degradation.
  • The compound enhanced MYC degradation, leading to reduced cancer cell growth in vitro and in vivo.
  • Enhanced apoptotic signaling was observed, correlating with MYC reduction.
  • 20S proteasome activation via TCH-165 was well tolerated in preclinical animal models.

Conclusions:

  • Small molecule-driven activation of the 20S proteasome represents a promising therapeutic strategy for MYC-driven cancers.
  • TCH-165 shows potential as a novel treatment for multiple myeloma by targeting MYC degradation.
  • Further investigation into 20S proteasome activators could lead to improved outcomes for patients with refractory or relapsing MM.
Keywords:
MYCchemotherapymultiple myelomanovel treatmentprotein degradationproteosome

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