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A rhodium(III)-based inhibitor of autotaxin with antiproliferative activity
Tian-Shu Kang1, Wanhe Wang2, Hai-Jing Zhong1
1State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, China.
Background:
Cancer of the skin is by far the most common of all cancers. Melanoma accounts for only about 1% of skin cancers but causes a large majority of skin cancer deaths. Autotaxin (ATX), also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), regulates physiological and pathological functions of lysophosphatidic acid (LPA), and is thus an important therapeutic target.
Methods:
We synthesized ten metal-based complexes and a novel cyclometalated rhodium(III) complex 1 was identified as an ATX enzymatic inhibitor using multiple methods, including ATX enzymatic assay, thermal shift assay, western immunoblotting and so on.
Results:
Protein thermal shift assays showed that 1 increased the melting temperature (Tm) of ATX by 3.5°C. 1 also reduced ATX-LPA mediated downstream survival signal pathway proteins such as ERK and AKT, and inhibited the activation of the transcription factor nuclear factor κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3). 1 also exhibited strong anti-proliferative activity against A2058 melanoma cells (IC50=0.58μM). Structure-activity relationship indicated that both the rhodium(III) center and the auxiliary ligands of complex 1 are important for bioactivity.
Conclusions:
1 represents a promising scaffold for the development of small-molecule ATX inhibitors for anti-tumor applications. To our knowledge, complex 1 is the first metal-based ATX inhibitor reported to date.
General Significance:
Rhodium complexes will have the increased attention in therapeutic and bioanalytical applications.
Insights
A novel rhodium(III) complex inhibits autotaxin (ATX), a key target in melanoma. This metal-based compound shows anti-proliferative effects on melanoma cells and offers a promising scaffold for new cancer therapies.
Area of Science:
- Medicinal Chemistry
- Oncology
- Materials Science
Background:
- Melanoma is a deadly skin cancer, and autotaxin (ATX) is a crucial therapeutic target.
- Autotaxin (ENPP2) regulates lysophosphatidic acid (LPA) in physiological and pathological processes.
Purpose of the Study:
- To develop novel metal-based autotaxin (ATX) inhibitors for anti-tumor applications.
- To investigate the potential of a novel cyclometalated rhodium(III) complex as an ATX inhibitor.
Main Methods:
- Synthesis of ten metal-based complexes, including a novel rhodium(III) complex.
- Utilized ATX enzymatic assays, thermal shift assays, and western immunoblotting to identify and characterize the inhibitor.
- Assessed anti-proliferative activity against A2058 melanoma cells.
Main Results:
- The rhodium(III) complex 1 demonstrated ATX enzymatic inhibition and increased ATX melting temperature by 3.5°C.
- Complex 1 reduced downstream survival signals (ERK, AKT) and inhibited transcription factors (NF-κB, STAT3).
- Exhibited potent anti-proliferative activity against melanoma cells with an IC50 of 0.58μM.
Conclusions:
- Complex 1 is the first reported metal-based ATX inhibitor, serving as a promising scaffold for small-molecule ATX inhibitors.
- Both the rhodium(III) center and auxiliary ligands are critical for the bioactivity of complex 1.
- Rhodium complexes warrant further attention for therapeutic and bioanalytical applications in cancer treatment.
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