Development of a SIN1 Targeting Inhibitor as a Novel Therapeutic Approach for the Treatment of Malignancies
The essential role of mTOR in promoting tumorigenesis of many cancers makes it an attractive therapeutic target. However, catalytic mTOR inhibitors, which block both mTORC1 and mTORC2, result in activation of negative feedback loops as a resistance mechanism. Selective mTORC2 inhibitors are expected to have the desired anti-tumor effects without engaging resistance mechanisms; however, to date, no such mTORC2 inhibitors have been developed. Using in-silico screening and medicinal chemistry optimization, we identified several small molecules that bind to the unique mTORC2 component, SIN1. We demonstrate that this SIN1 inhibitor alters post-translational modification, protein-protein interactions, and blocks mTORC2- and rapamycin sensitive (RS) mTORC1-mediated signaling. The SIN1 inhibitor also inhibits wildtype RAS activation and downstream MAPK signaling, as well as cell proliferation of multiple cancer cell line types. SIN1 inhibition can enhance the efficacy of FDA- approved anti-neoplastic agents in vitro and may provide a novel approach for the treatment of different types of malignancies.
Authors
- Connor Lantz (ORCID: https://orcid.org/0000-0003-3317-6486)
- Sara F. Dunne (ORCID: https://orcid.org/0000-0002-0273-680X)
- Diana Saleiro (ORCID: https://orcid.org/0000-0002-6756-3620)
- Mirage Modi (ORCID: https://orcid.org/0000-0001-5998-2107)
- Sara G. Radecki (ORCID: https://orcid.org/0000-0001-7585-8333)
- Eleanor N. Fish (ORCID: https://orcid.org/0000-0002-1292-4644)
- Lihua Zou (ORCID: https://orcid.org/0000-0003-0686-3117)
- Chidera V. Oku (ORCID: https://orcid.org/0000-0002-5846-1921)
- Matt Clutter
- Mariafausta Fischietti (ORCID: https://orcid.org/0000-0002-5691-689X)
- Elspeth M. Beauchamp (ORCID: https://orcid.org/0009-0007-3180-2742)
- Gary E. Schiltz (ORCID: https://orcid.org/0000-0003-4180-5051)
- Dominik A. Nahotko (ORCID: https://orcid.org/0000-0001-5349-1139)
- Gavin T. Blyth
- Emely Lopez Fajardo
- Purav P. Vagadia
- B. Cho
- Elena Karras
- Rama K. Mishra
- Leonidas C. Platanias
- Jenna Rossoff
- Sidharth Addepalli
- Young Ah Goo
- Atul Jain
- Alain Mina
Institutions
- Northwestern University (US)
- University Health Network (CA)
- University of Toronto (CA)
- Lurie Children's Hospital (US)
- Jesse Brown VA Medical Center (US)
- National Cancer Institute (US)
- High Throughput Biology (United States) (US)
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Publication Details
- Journal
- Molecular Cancer Therapeutics
- Published
- 2025-12-22
- DOI
- https://doi.org/10.1158/1535-7163.mct-25-0298
- Primary Topic
- PI3K/AKT/mTOR signaling in cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00