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

Kang, Tian-Shu, Wang, Wanhe, Zhong, Hai-Jing, Liang, Jia-Xin, Ko, Chung-Nga, Lu, Jin-Jian, Chen, Xiu-Ping, Ma, Dik-Lung, Leung, Chung-Hang
Biochimica et biophysica acta 2017 v.1861 no.2 pp. 256-263
immunoblotting, ligands, melanoma, melting point, mitogen-activated protein kinase, rhodium, signal transduction, skin neoplasms, structure-activity relationships, transactivators, transcription factor NF-kappa B, transcriptional activation
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.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.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.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.Rhodium complexes will have the increased attention in therapeutic and bioanalytical applications.