A rhodium(III)-based inhibitor of autotaxin with antiproliferative activity

Tian Shu Kang, Wanhe Wang, Hai Jing Zhong, Jia Xin Liang, Chung Nga Ko, Jin Jian Lu, Xiu Ping Chen, Edmond Dik Lung MA*, Chung Hang Leung

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)


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 = 0.58 μM). 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.

Original languageEnglish
Pages (from-to)256-263
Number of pages8
JournalBiochimica et Biophysica Acta - General Subjects
Issue number2
Publication statusPublished - 1 Feb 2017

Scopus Subject Areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

User-Defined Keywords

  • Anticancer
  • Autotaxin
  • Inhibitor
  • Melanoma
  • Rhodium complex


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