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Published on: April 22, 2019
Small-molecule inhibition of STAT3 in radioresistant head and neck squamous cell carcinoma
Uddalak Bharadwaj1, T Kris Eckols1, Xuejun Xu2
1Department of Infectious Disease, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Abstract:
While STAT3 has been validated as a target for treatment of many cancers, including head and neck squamous cell carcinoma (HNSCC), a STAT3 inhibitor is yet to enter the clinic. We used the scaffold of C188, a small-molecule STAT3 inhibitor previously identified by us, in a hit-to-lead program to identify C188-9. C188-9 binds to STAT3 with high affinity and represents a substantial improvement over C188 in its ability to inhibit STAT3 binding to its pY-peptide ligand, to inhibit cytokine-stimulated pSTAT3, to reduce constitutive pSTAT3 activity in multiple HNSCC cell lines, and to inhibit anchorage dependent and independent growth of these cells. In addition, treatment of nude mice bearing xenografts of UM-SCC-17B, a radioresistant HNSCC line, with C188-9, but not C188, prevented tumor xenograft growth. C188-9 treatment modulated many STAT3-regulated genes involved in oncogenesis and radioresistance, as well as radioresistance genes regulated by STAT1, due to its potent activity against STAT1, in addition to STAT3. C188-9 was well tolerated in mice, showed good oral bioavailability, and was concentrated in tumors. Thus, C188-9, either alone or in combination with radiotherapy, has potential for use in treating HNSCC tumors that demonstrate increased STAT3 and/or STAT1 activation.
Insights
A novel small-molecule inhibitor, C188-9, effectively targets STAT3 and STAT1 activation in head and neck squamous cell carcinoma (HNSCC) cells and tumors. This STAT3 inhibitor shows promise for treating radioresistant HNSCC, alone or with radiotherapy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Signal transducer and activator of transcription 3 (STAT3) is a validated therapeutic target in head and neck squamous cell carcinoma (HNSCC).
- Currently, no STAT3 inhibitors are available in clinical settings for cancer treatment.
- Previous research identified C188 as a small-molecule STAT3 inhibitor.
Purpose of the Study:
- To develop an improved STAT3 inhibitor based on the C188 scaffold.
- To evaluate the efficacy of the novel inhibitor, C188-9, against HNSCC in vitro and in vivo.
- To assess the potential of C188-9 in combination with radiotherapy for HNSCC treatment.
Main Methods:
- Utilized a hit-to-lead program to optimize the C188 scaffold, resulting in C188-9.
- Assessed C188-9's binding affinity to STAT3 and its ability to inhibit STAT3 phosphorylation and downstream signaling.
- Evaluated C188-9's anti-proliferative effects on HNSCC cell lines and its efficacy in a mouse xenograft model of radioresistant HNSCC.
- Investigated the impact of C188-9 on STAT3 and STAT1 regulated genes involved in oncogenesis and radioresistance.
Main Results:
- C188-9 demonstrated high affinity for STAT3 and superior inhibition of STAT3 activity compared to C188.
- C188-9 effectively inhibited HNSCC cell growth and prevented tumor growth in a radioresistant HNSCC xenograft model.
- C188-9 exhibited potent activity against both STAT3 and STAT1, modulating key oncogenic and radioresistance genes.
- The compound showed good oral bioavailability, tumor concentration, and was well tolerated in mice.
Conclusions:
- C188-9 is a potent STAT3 inhibitor with significant anti-cancer activity against HNSCC.
- C188-9's dual activity against STAT3 and STAT1 suggests broad applicability in HNSCC treatment.
- C188-9 holds potential as a therapeutic agent for HNSCC, particularly radioresistant tumors, as a standalone treatment or in combination with radiotherapy.
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