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Structure-Based Discovery of MolPort-137: A Novel Autotaxin Inhibitor That Improves Paclitaxel Efficacy
Prateek Rai1,2, Christopher J Clark1,2, Vandana Kardam3
1Molecular Biosciences, Middle Tennessee State University, Murfreesboro, TN 37132, USA.
Abstract:
The autotaxin-lysophosphatidic acid receptor (ATX-LPAR) signaling axis is pivotal in various clinical conditions, including cancer and autoimmune disorders. This axis promotes tumorigenicity by interacting with the tumor microenvironment, facilitating metastasis, and conceding antitumor immunity, thereby fostering resistance to conventional cancer therapies. Recent studies highlight the promise of ATX/LPAR inhibitors in combination with conventional chemotherapeutic drugs to overcome some forms of this resistance, representing a novel therapeutic strategy. In the current study, we employed structure-based virtual screening, integrating pharmacophore modeling and molecular docking, to identify MolPort-137 as a novel ATX inhibitor with an IC50 value of 1.6 ± 0.2 μM in an autotaxin enzyme inhibition assay. Molecular dynamics simulations and binding free energy calculations elucidated the binding mode of MolPort-137 and its critical amino acid interactions. Remarkably, MolPort-137 exhibited no cytotoxicity as a single agent but enhanced the effectiveness of paclitaxel in 4T1 murine breast carcinoma cells and resensitized taxol-resistant cells to paclitaxel treatment, which highlights its potential in combination therapy.
Insights
A novel autotaxin (ATX) inhibitor, MolPort-137, was identified and showed promise in overcoming cancer therapy resistance. It enhanced paclitaxel effectiveness in breast cancer cells, suggesting potential for combination treatments.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- The autotaxin-lysophosphatidic acid receptor (ATX-LPAR) signaling axis is implicated in cancer progression, metastasis, and resistance to conventional therapies.
- Targeting the ATX-LPAR axis offers a potential strategy to overcome treatment resistance in various cancers.
Purpose of the Study:
- To identify novel autotaxin (ATX) inhibitors using structure-based virtual screening.
- To evaluate the therapeutic potential of identified inhibitors, particularly in combination with chemotherapy.
Main Methods:
- Structure-based virtual screening, pharmacophore modeling, and molecular docking were employed to identify ATX inhibitors.
- Autotaxin enzyme inhibition assays, molecular dynamics simulations, and binding free energy calculations were used to characterize inhibitor binding.
- Cytotoxicity assays and in vitro studies with 4T1 murine breast carcinoma cells were conducted to assess efficacy and combination effects.
Main Results:
- MolPort-137 was identified as a novel ATX inhibitor with an IC50 of 1.6 ± 0.2 μM.
- Molecular dynamics simulations revealed key amino acid interactions of MolPort-137 with autotaxin.
- MolPort-137 demonstrated no cytotoxicity as a single agent but enhanced paclitaxel efficacy and resensitized resistant cells.
Conclusions:
- MolPort-137 is a promising novel ATX inhibitor with potential for combination therapy in cancer treatment.
- This study highlights the therapeutic potential of targeting the ATX-LPAR axis to overcome chemotherapy resistance, particularly in breast cancer.
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