IB-MECA and its structural analogs, A3 adenosine receptor (AR) agonists have been clinically developed to treat human diseases such as hepatocellular carcinoma, psoriasis and rheumatoid arthritis. Recently, the effects of ARs on metabolic disease such as type Ⅱ diabetes and obesity have been also studied.One of phenotype-based assays, the induction of adipogenesis in human bone marrow mesenchymal stem cells (hBM-MSCs) is utilized to drug screening for metabolic diseases. IB-MECA promoted the production of adiponectin during adipogenesis in hBM-MSCs, associated with the improvement of insulin sensitivity. Its structural analogs, both A3 AR agonists and A3 AR antagonists showed similar activities in hBM-MSCs indicating adipogenesis is mediated by off-target. In a target deconvolution study, IB-MECA and its structural analogs have binding activities to both peroxisome proliferator activated receptor (PPAR)γ and PPARδ. The important thing is that the adiponectin-promoting activity of IB-MECA and its structural analogs significantly correlated with PPARγ and PPARδ binding affinity. Conclusively, we elucidated that IB-MECA and its structural analogs play roles as both PPARγ partial agonists and PPARδ antagonists. In the streptozotocin (STZ)-induced diabetic C57BL/6J mice model, the most potent IB-MECA structural analog significantly improved serum glucose and triglyceride indicating anti-diabetic potential. Together, our finding reveals that the polypharmacological feature of IB-MECA and its structural analogs suggests a therapeutic insight against human metabolic diseases.
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Target deconvolution of active molecules to regulate adipogenesis in human mesenchymal stem cells
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