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Published on: May 20, 2015
Discovery of novel STAT3 inhibitors with anti-breast cancer activity: structure-based virtual screening, molecular
Jinhui Wang1, Peijie Zhang2, Yalin Yu3
1Donghai Laboratory Zhoushan Zhejiang 316021 China.
Abstract:
Triple negative breast cancer (TNBC) is a fatal type of breast cancer due to its high recurrence and metastatic potential. Persistent activation of signal transducer and activator of transcription 3 (STAT3) is crucial for TNBC progression, making it an attractive drug target. In this study, two new STAT3 inhibitors with significant anti-TNBC activity, d2 and d10, were identified from 1.67 million candidates through a rapid and cost-effective strategy integrating high-throughput virtual screening (HTVS), molecular mechanics/generalized born surface area (MM/GBSA), and binding pose metadynamics (BPMD) methods. In-depth mechanistic studies revealed that d2 and d10 significantly inhibited cell proliferation and colony formation, induced G1 phase arrest, and reduced migration and invasion of TNBC cells. Moreover, both d2 and d10 were found to inhibit the nuclear translocation and phosphorylation of STAT3. Molecular dynamics simulations further indicated that both compounds can stably bind to STAT3 in the SH2 domain. Additionally, protein-ligand interaction fingerprints (IFPs) of the screened compounds from HTVS were generated to better guide the design and structural optimization of STAT3 inhibitors.
Insights
Two novel compounds, d2 and d10, effectively inhibit signal transducer and activator of transcription 3 (STAT3) in triple-negative breast cancer (TNBC) cells, offering a promising new therapeutic strategy for this aggressive disease.
Area of Science:
- Oncology
- Medicinal Chemistry
- Computational Biology
Background:
- Triple-negative breast cancer (TNBC) presents a significant clinical challenge due to its aggressive nature, high recurrence rates, and limited targeted therapies.
- Persistent activation of signal transducer and activator of transcription 3 (STAT3) is a key driver of TNBC progression and metastasis, identifying it as a critical therapeutic target.
Purpose of the Study:
- To identify novel small molecules that inhibit STAT3 signaling for the potential treatment of triple-negative breast cancer.
- To elucidate the mechanism of action of newly identified STAT3 inhibitors against TNBC cells.
Main Methods:
- A multi-stage computational strategy combining high-throughput virtual screening (HTVS), molecular mechanics/generalized Born surface area (MM/GBSA), and binding pose metadynamics (BPMD) was employed.
- In vitro assays were conducted to assess the effects of identified compounds on TNBC cell proliferation, colony formation, cell cycle progression, migration, and invasion.
- Western blotting and molecular dynamics simulations were utilized to investigate the inhibition of STAT3 phosphorylation, nuclear translocation, and binding affinity.
Main Results:
- Two potent STAT3 inhibitors, designated d2 and d10, were identified from a large virtual library of over 1.67 million compounds.
- Compounds d2 and d10 demonstrated significant anti-proliferative and anti-metastatic effects in TNBC cells, inducing G1 phase arrest and reducing cell migration and invasion.
- Mechanistic studies confirmed that d2 and d10 inhibit STAT3 phosphorylation and nuclear translocation, with molecular dynamics simulations showing stable binding to the STAT3 SH2 domain.
Conclusions:
- The identified compounds d2 and d10 represent promising lead candidates for the development of novel therapeutics targeting STAT3 in triple-negative breast cancer.
- The integrated computational screening approach proved effective and cost-efficient for identifying potent drug candidates.
- Generated protein-ligand interaction fingerprints (IFPs) can guide future optimization of STAT3 inhibitors.
