Discovery of pan-EphB tyrosine kinase inhibitor for metabolic syndrome sparing EphB3 signaling in mice.

The global prevalence of metabolic syndrome had created one of the most pressing public health dilemmas and significant financial burden to the healthcare system. Despite the surge of glucagon-like peptide-1 agonists, recent studies showed that 40 % of body weight loss is due to lean mass loss, raising the concern about induction of musculoskeletal arthritis. Therefore, there is an urgent need to develop novel therapeutic strategies to tackle the progression of metabolic disorders with minimal adverse effects. EphB singaling had been validated in the progression of metabolic syndrome. We leveraged the resolved X-ray crystal structure of the hEphB1 kinase domain to introduce thienopyridine-based analogs (termed STA analogs) that showed potential pan-inhibitory profiles for EphB1, EphB2, and EphB4 with no inhibition for EphB3 tyrosine kinase singaling pathways. STA-013 inhibited EphB1, EphB2, and EphB4 tyrosine kinases selectively, as validated by a premier kinase profiling assay against 140 protein kinases, with no inhibitory profile against EphB3 tyrosine kinase. Systemic injections of STA-013 resulted in weight loss with significant reduction of fat mass and perseverance of lean mass. This was associated with significant improvement in glucose homeostasis, mitigation of insulin resistance, and inhibition of fatty liver in high-fat diet-induced obese mice. This was allied with modulation of respiratory exchange rates during the dark cycle, with no change in food intake. Additionally, STA-013 administration resulted in inhibiting the EphB phosphorylated signal, coupled with increased p-AKT/AKT signaling, to suggest insulin signaling activation. STA-013 showed an elevated signal for InsR-β, which reversed the effect of insulin on InsR degradation, allowing for the restoration of glucose homeostasis and mitigating insulin resistance.