title: A rhodium(III)-based inhibitor of autotaxin with antiproliferative activity.
abstract: 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.
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, China.
authors.forename: Tian-Shu
authors.initials: TS
authors.lastname: Kang
authors.affiliation: Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.
authors.forename: Wanhe
authors.initials: W
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, China.
authors.forename: Hai-Jing
authors.initials: HJ
authors.lastname: Zhong
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, China.
authors.forename: Jia-Xin
authors.initials: JX
authors.lastname: Liang
authors.affiliation: Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.
authors.forename: Chung-Nga
authors.initials: CN
authors.lastname: Ko
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, China.
authors.forename: Jin-Jian
authors.initials: JJ
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, China.
authors.forename: Xiu-Ping
authors.initials: XP
authors.lastname: Chen
authors.affiliation: Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China. Electronic address: edmondma@hkbu.edu.hk.
authors.forename: Dik-Lung
authors.initials: DL
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, China. Electronic address: duncanleung@umac.mo.
authors.forename: Chung-Hang
authors.initials: CH
authors.lastname: Leung
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D043264:Phosphodiesterase I / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D012238:Rhodium / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D000099189:Lysophospholipase D
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D008246:Lysophospholipids; D009097:Multienzyme Complexes; D016328:NF-kappa B; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases; D012238:Rhodium; D050796:STAT3 Transcription Factor; D000099189:Lysophospholipase D; C032881:lysophosphatidic acid
keywords: Anticancer; Autotaxin; Inhibitor; Melanoma; Rhodium complex