Small molecule disruption of RARα/NCoR1 interaction inhibits chaperone-mediated autophagy in cancer

Area of Science:

• Molecular Biology
• Cancer Research
• Drug Discovery

Background:

• Chaperone-mediated autophagy (CMA) is upregulated in cancer, aiding cell survival.
• Targeting CMA is challenging due to the lack of specific inhibitors, often requiring genetic methods or broad lysosomal inhibition.

Purpose of the Study:

• To investigate the regulatory role of retinoic acid receptor alpha (RARα) and nuclear receptor corepressor 1 (NCoR1) interaction on CMA in non-small cell lung cancer (NSCLC).
• To identify a novel, selective inhibitor of CMA for potential therapeutic application in NSCLC.

Main Methods:

• Genetic modulation, transcriptional analysis, and functional studies were employed.
• Structure-based screening was used to identify compounds targeting the NCoR1/RARα complex.
• In vitro assays assessed compound selectivity and efficacy in NSCLC cells.
• In vivo xenograft mouse models evaluated therapeutic efficacy and toxicity.

Main Results:

• The interaction between RARα and NCoR1 was found to regulate CMA in NSCLC.
• Compound CIM7 was identified as a potent and selective inhibitor of CMA, distinct from macroautophagy.
• CIM7 demonstrated preferential inhibition of CMA in NSCLC cells compared to normal cells.
• CIM7 reduced tumor growth in NSCLC models and showed efficacy in vivo without significant toxicity.

Conclusions:

• A druggable mechanism for selective CMA inhibition was revealed through the NCoR1/RARα complex.
• Compound CIM7 represents a first-in-class CMA inhibitor with therapeutic potential for NSCLC.
• Targeting CMA via CIM7 offers a novel strategy for NSCLC treatment.