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A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds
Published on: April 6, 2016
Discovery of ERBB3 inhibitors for non-small cell lung cancer (NSCLC) via virtual screening
Rong Guo1, Yuan Zhang1, Xiao Li1
1Beijing Computing Center, NO.7 Fengxian Middle St, Haidian District, Beijing, 100094, China.
Abstract:
As a member of the epidermal growth factor receptor family (EGFR) of receptor tyrosine kinases, ERBB3 plays an important role in mediating cellular growth and differentiation. Recent research works identified that CD74-NRG1 fusions lead to overexpression of the EGF-like domain of NRG1, and thus activate ERBB3 and PI3K-AKT signaling pathways. The fusion was detected in lung adenocarcinomas, and served as an important oncogenic factor for ERBB3 driven cancers. A sequential virtual screening strategy has been applied to ERBB3 crystal structure using databases of natural products and Chinese traditional medicine compounds, and led to identification of a group of small molecular compounds potentially capable of blocking ERBB3. Six small molecular compounds were selected for in vitro analysis. Five of these molecules significantly inhibited the growth of A549 cells. Among them, compound VS1 is the most promising one with IC50 values of 269.75 μM, comparing to the positive control of nimustine hydrochloride with IC50 values of 264.14 μM. With good specificity and predicted ADMET results, our results support the feasibility by using a pharmacophore of the compound VS1 for designing and optimization of ERBB3 inhibitors.
Insights
Researchers identified small molecules that inhibit ERBB3, a key factor in lung adenocarcinoma. Compound VS1 shows promise as a potential ERBB3 inhibitor for cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- ERBB3 is an epidermal growth factor receptor family member crucial for cell growth.
- CD74-NRG1 fusions activate ERBB3 and PI3K-AKT pathways, driving lung adenocarcinomas.
- ERBB3 is an important oncogenic factor in ERBB3-driven cancers.
Purpose of the Study:
- To identify small molecular compounds capable of blocking ERBB3.
- To evaluate the efficacy of identified compounds against ERBB3-driven cancer cells.
Main Methods:
- Virtual screening of natural products and Chinese traditional medicine compounds against ERBB3 crystal structure.
- In vitro analysis of selected small molecular compounds using A549 lung cancer cells.
- Determination of IC50 values and assessment of specificity and ADMET properties.
Main Results:
- Six small molecular compounds were identified as potential ERBB3 inhibitors.
- Five compounds significantly inhibited A549 cell growth.
- Compound VS1 demonstrated promising efficacy with an IC50 of 269.75 μM, comparable to nimustine hydrochloride.
Conclusions:
- Small molecules, particularly VS1, show potential for developing novel ERBB3 inhibitors.
- The pharmacophore of VS1 can guide the design and optimization of targeted cancer therapies.
- This study supports the feasibility of targeting ERBB3 for cancer treatment.
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