Endomorphin-2

Lung cancer, 85% of which is non‐small cell lung cancer (NSCLC), is the cancer with the highest incidence and mortality rate worldwide. Despite recent advancements in therapeutic approaches, the efficacy of conventional radiotherapy and chemotherapy remains suboptimal, highlighting the urgent need for more effective treatment strategies. Dysregulation of kinases MST1 and MST2 (MST1/2) is implicated in the progression of NSCLC, positioning MST1/2 as a potential therapeutic target. However, no high‐selectivity and high‐efficacy MST1/2 activator is identified to date. In this study, by using computer‐aided virtual screening combined with cell experiments, EM2 is identified as a promising MST1/2‐binding candidate. Subsequent experimental validation demonstrates that EM2 significantly suppresses the proliferation, migration, and invasion of NSCLC cells by directly targeting MST1/2 and enhancing its kinase activity, thereby activating the Hippo signaling pathway and reducing nuclear translocation of the downstream effector YAP. Both in vivo xenograft models and organoid models demonstrates that EM2 effectively suppresses NSCLC tumor growth. In summary, this study not only reaffirms MST1/2 as a viable therapeutic target for NSCLC but also provides compelling experimental evidence supporting EM2 as a highly effective and promising anti‐cancer agent.

The µ-opioid receptor (µ-OR) is the key target for morphine in the treatment of (chronic) pain. Endogenous opioids at the µ-OR have been implicated in multiple physiological processes, including pain relief. However, the extent to which µ-OR occupancy of morphine is influenced by endogenous opioids and µ-OR internalization is unclear. The aim of this study was to investigate the impact of endogenous opioids and µ-OR internalization on morphine µ-OR occupancy. To this end we developed a mathematical binding kinetic model incorporating information on binding kinetic parameters, µ-OR expression, µ-OR internalization rates, and levels of multiple endogenous opioids, in rat hypothalamus. µ-OR occupancies were simulated using morphine brain extracellular fluid concentration data, for different static levels of the endogenous opioids, including beta-endorphin, Dynorphin-A 1-17, Endomorphin-2, Leu-enkephalin, and Met-enkephalin. Simulations were performed in absence or presence of µ-OR internalization. We show that beta-endorphin has a strong impact on morphine µ-OR occupancy, followed by limited impact of met-enkephalin. Other endogenous opioids did not demonstrate any significant effect. µ-OR internalization reduced the impact of beta-endorphin on morphine µ-OR occupancy to a limited extent. We conclude that beta-endorphin plays an important role in morphine µ-OR occupancy, which could therefore play a key role in explaining interindividual variability in the analgesic effects of morphine. Finally, this study demonstrates the utility of a mathematical model workflow in deciphering the role of endogenous ligands in morphine's µ-OR occupancy.