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Published on: December 26, 2016
Structure-Based Virtual Screening, Synthesis and Biological Evaluation of Potential FAK-FAT Domain Inhibitors for
Sahar B Kandil1, Samuel R Jones1, Sonia Smith1
1School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Wales CF10 3NB, UK.
Abstract:
Focal adhesion kinase (FAK) is a tyrosine kinase that is overexpressed and activated in several advanced-stage solid cancers. In cancer cells, FAK promotes the progression and metastasis of tumours. In this study, we used structure-based virtual screening to filter a library of more than 210K compounds against the focal adhesion targeting FAK-focal adhesion targeting (FAT) domain to identify 25 virtual hit compounds which were screened in the invasive breast cancer line (MDA-MB-231). Most notably, compound I showed low micromolar antiproliferative activity, as well as antimigratory activity. Moreover, examination in a model of triple negative breast cancer (TNBC), revealed that, despite not effecting FAK phosphorylation, compound I significantly impairs proliferation whilst impairing focal adhesion growth and turnover leading to reduced migration. Further optimisation and synthesis of analogues of the lead compound I using a four-step synthetic procedure was performed, and analogues were assessed for their antiproliferative activity against three breast cancer (MDA-MB-231, T47D, BT474) cell lines and one pancreatic cancer (MIAPaCa2) cell line. Compound 5f was identified as a promising lead compound with IC50 values in the range of 4.59-5.28 microM in MDA-MB-231, T47D, BT474, and MIAPaCa2. Molecular modelling and pharmacokinetic studies provided more insight into the therapeutic features of this new series.
Insights
Researchers identified a new compound, compound 5f, that shows promise in inhibiting the growth and migration of triple-negative breast cancer cells by targeting focal adhesion kinase (FAK). This discovery offers a potential new therapeutic strategy for advanced solid cancers.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Focal adhesion kinase (FAK) is a tyrosine kinase implicated in the progression and metastasis of advanced solid cancers.
- Overexpression and activation of FAK are observed in several cancer types, making it a potential therapeutic target.
Purpose of the Study:
- To identify novel small molecules targeting the FAK-FAT domain for cancer therapy.
- To evaluate the antiproliferative and antimigratory effects of identified compounds in breast and pancreatic cancer models.
Main Methods:
- Structure-based virtual screening of over 210,000 compounds against the FAK-FAT domain.
- In vitro screening of hit compounds using invasive breast cancer cell lines (MDA-MB-231).
- Synthesis and assessment of analogues, including compound 5f, for antiproliferative activity against multiple cancer cell lines (MDA-MB-231, T47D, BT474, MIAPaCa2).
Main Results:
- Compound I demonstrated low micromolar antiproliferative and antimigratory activity in MDA-MB-231 cells.
- Compound I impaired proliferation and focal adhesion dynamics in triple-negative breast cancer models, reducing migration without affecting FAK phosphorylation.
- Compound 5f emerged as a promising lead with IC50 values between 4.59-5.28 microM across tested cancer cell lines.
Conclusions:
- Compound 5f represents a potential therapeutic lead for breast and pancreatic cancers, targeting FAK-mediated pathways.
- Further optimization and investigation of compound 5f and its analogues are warranted for their anticancer potential.
- The study highlights the utility of structure-based virtual screening in identifying novel FAK inhibitors.
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