Obesity is a chronic disease of high prevalence, up to 42.4%, resulting in a significant financial burden to the US healthcare system. Current estimates highlight the epidemic status of obesity up to 57% globally. The significant consequences of obesity are associated with the progression of various chronic disorders such as hyperglycemia, type 2 diabetes (T2D), dyslipidemia, cardiovascular disease, and heart failure. EphB tyrosine kinase receptor and its cognate ligand, Ephrin-B, have recently emerged as a promising target implicated in numerous pathologies, including Alzheimer’s disease, anxiety, neuropathic pain, malignancies, fibrotic diseases, and viral infections. Previous studies validated the role of EphB4 tyrosine kinase in insulin signaling, where genetic inhibition of EphB4 improved insulin resistance and glucose intolerance in obese mice. Herein, we report the in silico molecular simulations, synthesis, and structural optimization of a series of 24 thienopyridine-based analogues (termed STA analogues). Furthermore, STA-based analogs showed potential binding and pan-inhibition for EphB tyrosine kinase signaling at nanomolar ranges using ADP-Glo assays. This was followed by in vivo biological evaluation for STA-013 in diet-induced obesity mouse models. STA-013 revealed promising inhibitory profiles against EphB1 (IC₅₀= 900 nM), EphB2 (IC₅₀= 3.50 µM), and EphB4 (IC₅₀= 1.05 µM) tyrosine kinases. Our in vivo studies showed that STA-013 induced whole-bodyweight loss and improved glucose homeostasis significantly in high-fat diet (HFD)-induced obesity mouse models. Our findings will elucidate the first-in-class potent pan-EphB tyrosine kinase inhibitors and their mechanistic role in mitigating obesity and associated metabolic disorders.

Syed Mohammed Tareq

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