2. Academic Validation
  3. Novel PROTAC probes targeting FOSL1 degradation to eliminate head and neck squamous cell carcinoma cancer stem cells

Novel PROTAC probes targeting FOSL1 degradation to eliminate head and neck squamous cell carcinoma cancer stem cells

  • Bioorg Chem. 2024 Jul 9:151:107613. doi: 10.1016/j.bioorg.2024.107613.
Shadid U Zaman 1,  Piyusha P Pagare 2,  Boshi Huang 3,  Grace Rilee 4,  Zhikun Ma 5,  Yan Zhang 6,  Jiong Li 7
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298-0540, United States. Electronic address: zamans@vcu.edu.
  • 2 Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298-0540, United States. Electronic address: pagarepp@vcu.edu.
  • 3 Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298-0540, United States. Electronic address: hma@vcu.edu.
  • 4 Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298-0540, United States. Electronic address: rileegj@vcu.edu.
  • 5 Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298-0540, United States. Electronic address: maz2@vcu.edu.
  • 6 Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298-0540, United States; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298-0540, United States. Electronic address: yzhang2@vcu.edu.
  • 7 Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298-0540, United States; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298-0540, United States; Department of Oral and Craniofacial Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298-0540, United States. Electronic address: jli29@vcu.edu.
PMID: 39002513 DOI: 10.1016/j.bioorg.2024.107613
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.

Keywords

AP-1; Cancer stem cell; FOSL1; HNSCC; PROTAC.

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