1. Novel PROTAC probes targeting FOSL1 degradation to eliminate head and neck squamous cell carcinoma cancer stem cells.
- Author
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Zaman SU, Pagare PP, Huang B, Rilee G, Ma Z, Zhang Y, and Li J
- Subjects
- Humans, Molecular Structure, Structure-Activity Relationship, Dose-Response Relationship, Drug, Cell Proliferation drug effects, Drug Screening Assays, Antitumor, Proteolysis drug effects, Cell Line, Tumor, Animals, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells metabolism, Proto-Oncogene Proteins c-fos metabolism, Proto-Oncogene Proteins c-fos antagonists & inhibitors, Squamous Cell Carcinoma of Head and Neck drug therapy, Squamous Cell Carcinoma of Head and Neck pathology, Squamous Cell Carcinoma of Head and Neck metabolism, Head and Neck Neoplasms drug therapy, Head and Neck Neoplasms pathology, Head and Neck Neoplasms metabolism, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents chemical synthesis
- Abstract
Previously, we identified that AP-1 transcription factor FOSL1 is required to maintain cancer stem cells (CSCs) in HNSCC, and an AP-1 inhibitor, T-5224, can eliminate HNSCC CSCs. However, its potency is relatively low, and furthermore, whether T-5224 eradicates CSCs through targeting FOSL1 and whether FOSL1 serves as an effective target for eliminating CSCs in HNSCC, require further validation. We first found that T-5224 can bind to FOSL1 directly. As a proof-of-principle, several cereblon (CRBN)-recruiting PROTACs were designed and synthesized using T-5224 as a warhead for more effective of targeting FOSL1. The top compound can potently degrade FOSL1 in HNSCC, thereby effectively eliminating CSCs to suppress HNSCC tumorigenesis, with around 30 to 100-fold improved potency over T-5224. In summary, our study further validates FOSL1 as an effective target for eliminating CSCs in HNSCC and suggests that PROTACs may provide a unique molecular tool for the development of novel molecules for targeting FOSL1., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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