Small molecule disruption of RARα/NCoR1 interaction inhibits chaperone-mediated autophagy in cancer
Abstract Chaperone-mediated autophagy (CMA), a type of selective degradation of cytosolic proteins in lysosomes, is commonly upregulated in cancer cells, contributing to their survival and growth. The lack of a specific target for CMA inhibition has limited CMA blockage to genetic manipulations or g...
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Springer Nature
2025-06-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.1038/s44321-025-00254-y |
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| author | Mericka McCabe Rajanya Bhattacharyya Rebecca Sereda Olaya Santiago-Fernández Rabia R Khawaja Antonio Diaz Kristen Lindenau Deniz Gulfem Ozturk Thomas P Garner Simone Sidoli Ana Maria Cuervo Evripidis Gavathiotis |
| author_facet | Mericka McCabe Rajanya Bhattacharyya Rebecca Sereda Olaya Santiago-Fernández Rabia R Khawaja Antonio Diaz Kristen Lindenau Deniz Gulfem Ozturk Thomas P Garner Simone Sidoli Ana Maria Cuervo Evripidis Gavathiotis |
| author_sort | Mericka McCabe |
| collection | DOAJ |
| description | Abstract Chaperone-mediated autophagy (CMA), a type of selective degradation of cytosolic proteins in lysosomes, is commonly upregulated in cancer cells, contributing to their survival and growth. The lack of a specific target for CMA inhibition has limited CMA blockage to genetic manipulations or global lysosomal function inhibition. Here, using genetic modulation, transcriptional analysis, and functional studies, we demonstrate a regulatory role for the interaction of the retinoic acid receptor alpha (RARα) and its corepressor, the nuclear receptor corepressor 1 (NCoR1), on CMA in non-small cell lung cancer (NSCLC). By targeting the disruption of the NCoR1/RARα complex with a structure-based screening strategy, we identified compound CIM7, a potent and selective CMA inhibitor that has no effect on macroautophagy. CIM7 preferentially inhibits CMA in NSCLC cells over normal cells, reduces tumor growth in NSCLC cells, and demonstrates efficacy in an in vivo xenograft mouse model with no observed toxicity in blood or major tissues. These findings reveal a druggable mechanism for selective CMA inhibition and a first-in-class CMA inhibitor as a potential therapeutic strategy for NSCLC. |
| format | Article |
| id | doaj-art-0a7e4bc06a6044e685f9b2d73a401ea5 |
| institution | Kabale University |
| issn | 1757-4684 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-0a7e4bc06a6044e685f9b2d73a401ea52025-08-20T04:02:55ZengSpringer NatureEMBO Molecular Medicine1757-46842025-06-011771716175510.1038/s44321-025-00254-ySmall molecule disruption of RARα/NCoR1 interaction inhibits chaperone-mediated autophagy in cancerMericka McCabe0Rajanya Bhattacharyya1Rebecca Sereda2Olaya Santiago-Fernández3Rabia R Khawaja4Antonio Diaz5Kristen Lindenau6Deniz Gulfem Ozturk7Thomas P Garner8Simone Sidoli9Ana Maria Cuervo10Evripidis Gavathiotis11Department of Biochemistry, Albert Einstein College of MedicineDepartment of Biochemistry, Albert Einstein College of MedicineDepartment of Developmental and Molecular Biology, Albert Einstein College of MedicineDepartment of Developmental and Molecular Biology, Albert Einstein College of MedicineDepartment of Developmental and Molecular Biology, Albert Einstein College of MedicineDepartment of Developmental and Molecular Biology, Albert Einstein College of MedicineDepartment of Developmental and Molecular Biology, Albert Einstein College of MedicineDepartment of Biochemistry, Albert Einstein College of MedicineDepartment of Biochemistry, Albert Einstein College of MedicineDepartment of Biochemistry, Albert Einstein College of MedicineDepartment of Developmental and Molecular Biology, Albert Einstein College of MedicineDepartment of Biochemistry, Albert Einstein College of MedicineAbstract Chaperone-mediated autophagy (CMA), a type of selective degradation of cytosolic proteins in lysosomes, is commonly upregulated in cancer cells, contributing to their survival and growth. The lack of a specific target for CMA inhibition has limited CMA blockage to genetic manipulations or global lysosomal function inhibition. Here, using genetic modulation, transcriptional analysis, and functional studies, we demonstrate a regulatory role for the interaction of the retinoic acid receptor alpha (RARα) and its corepressor, the nuclear receptor corepressor 1 (NCoR1), on CMA in non-small cell lung cancer (NSCLC). By targeting the disruption of the NCoR1/RARα complex with a structure-based screening strategy, we identified compound CIM7, a potent and selective CMA inhibitor that has no effect on macroautophagy. CIM7 preferentially inhibits CMA in NSCLC cells over normal cells, reduces tumor growth in NSCLC cells, and demonstrates efficacy in an in vivo xenograft mouse model with no observed toxicity in blood or major tissues. These findings reveal a druggable mechanism for selective CMA inhibition and a first-in-class CMA inhibitor as a potential therapeutic strategy for NSCLC.https://doi.org/10.1038/s44321-025-00254-yAutophagyCMA InhibitorNCoR1Non-small Cell Lung CancerRARα |
| spellingShingle | Mericka McCabe Rajanya Bhattacharyya Rebecca Sereda Olaya Santiago-Fernández Rabia R Khawaja Antonio Diaz Kristen Lindenau Deniz Gulfem Ozturk Thomas P Garner Simone Sidoli Ana Maria Cuervo Evripidis Gavathiotis Small molecule disruption of RARα/NCoR1 interaction inhibits chaperone-mediated autophagy in cancer EMBO Molecular Medicine Autophagy CMA Inhibitor NCoR1 Non-small Cell Lung Cancer RARα |
| title | Small molecule disruption of RARα/NCoR1 interaction inhibits chaperone-mediated autophagy in cancer |
| title_full | Small molecule disruption of RARα/NCoR1 interaction inhibits chaperone-mediated autophagy in cancer |
| title_fullStr | Small molecule disruption of RARα/NCoR1 interaction inhibits chaperone-mediated autophagy in cancer |
| title_full_unstemmed | Small molecule disruption of RARα/NCoR1 interaction inhibits chaperone-mediated autophagy in cancer |
| title_short | Small molecule disruption of RARα/NCoR1 interaction inhibits chaperone-mediated autophagy in cancer |
| title_sort | small molecule disruption of rarα ncor1 interaction inhibits chaperone mediated autophagy in cancer |
| topic | Autophagy CMA Inhibitor NCoR1 Non-small Cell Lung Cancer RARα |
| url | https://doi.org/10.1038/s44321-025-00254-y |
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