Amide-sulfamide modulators as effective anti-tumor metastatic agents targeting CXCR4/CXCL12 axis
Rui Wu1, Wenyan Yu1, Chuansheng Yao1
1College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, China.
Abstract:
Breast cancer is the most frequently diagnosed malignancy and the second common cause of death in women worldwide. High mortality in breast cancer is frequently associated with metastatic progression rather than the primary tumor itself. It has been recently identified that the CXCR4/CXCL12 axis plays a pivotal role in breast cancer metastasis, especially in directing metastatic cancer cells to CXCL12-riched organs and tissues. Herein, taking the amide-sulfamide as the lead structure, the second-round structural modifications to the sulfamide structure were performed to obtain more active CXCR4 modulators against tumor metastasis. Both in vivo and in vitro experiments illustrated that compound IIIe possessed potent CXCR4 binding affinity, excellent anti-metastatic and anti-angiogenetic activity against breast cancer. More importantly, in a mouse breast cancer lung metastasis model, compound IIIe exerted a significant inhibitory effect on breast cancer metastasis. Taken together, all these positive results demonstrated that developing of CXCR4 modulators is a promising strategy to mediate breast cancer metastasis.
Insights
Researchers developed novel CXCR4 modulators to combat breast cancer metastasis. Compound IIIe showed significant anti-metastatic and anti-angiogenetic effects in preclinical models, highlighting CXCR4 modulation as a promising therapeutic strategy.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Breast cancer is a leading cause of cancer death globally, with metastasis being the primary driver of mortality.
- The CXCR4/CXCL12 signaling axis is critically involved in directing breast cancer cell metastasis to specific organs.
- Targeting the CXCR4/CXCL12 pathway presents a potential strategy to inhibit cancer spread.
Purpose of the Study:
- To design and synthesize novel CXCR4 modulators based on an amide-sulfamide lead structure.
- To evaluate the anti-metastatic and anti-angiogenetic potential of these compounds against breast cancer.
- To investigate the efficacy of the lead compound in preclinical models of breast cancer metastasis.
Main Methods:
- Medicinal chemistry: Second-round structural modifications of amide-sulfamide derivatives.
- In vitro assays: Assessment of CXCR4 binding affinity and anti-angiogenetic activity.
- In vivo studies: Evaluation of anti-metastatic efficacy in a mouse breast cancer lung metastasis model.
Main Results:
- Compound IIIe demonstrated potent binding affinity to CXCR4.
- Compound IIIe exhibited significant anti-metastatic and anti-angiogenetic activities in vitro.
- Compound IIIe effectively inhibited breast cancer lung metastasis in a preclinical mouse model.
Conclusions:
- The developed CXCR4 modulators, particularly compound IIIe, show promise for inhibiting breast cancer metastasis.
- Targeting the CXCR4/CXCL12 axis is a viable therapeutic strategy for managing metastatic breast cancer.
- Further development of CXCR4 modulators could lead to novel treatments for advanced breast cancer.
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