The JAK/STAT pathway is known to play a role in multiple cellular stress conditions, including hypoxia, and pharmacological inhibition of both JAK2 and STAT3 was recently shown to promote satellite cell expansion during the early stages of muscle repair . Interestingly, it has been shown that GSK3�� antagonizes both HIF-1�� protein accumulation and the autophagic pathway in hypoxia conditions and promotes apoptosis through activation of caspase-3 and release of cytochrome c from the mitochondria . Indeed, efficient GSK3 inhibitors have been shown to promote cell survival in several stress conditions . Our fully factorial studies verified the effectiveness of combinatorial approaches while pathway analysis revealed a few MK-5172 important pathways associated with hypoxia-induced myoblast death. In particular, our study shows that CDK5 is at the center of the target network. The KIEN regression model also predicted CDK5 as a key target kinase that has protective impact on the cells in hypoxia when the resulting coefficients were ranked. Interestingly, KIEN analysis also OT-R antagonist 2 structure ranked CDK5 highly when performed for the HT22 neuronal cell line, suggesting that CDK inhibition might be a general protective mechanism relevant to hypoxia in more than one tissue. The important role of CDK5 in hypoxia-associated cell death has previously been described, supporting our findings . Albeit in non-myoblast cells, CDK5 was reported to control ischemic/hypoxic damage and mediate excitotoxic neuronal cell death . For example, viral-mediated dominant negative CDK5 expression was shown to inhibit death induced by hypoxia in a mouse stroke model . In addition, the protective efficacy of CDK and GSK3 inhibitor was reported in hypoxia-ischemia mouse model . CDK and GSK3 are two important targets linking the candidate inhibitors from our analysis. Taken together, these literatures support the validity of our regression model that identified CDK5 as a key kinase from the kinase inhibitor library screening. In the future, we could simultaneously target the highly ranked kinases in combination with CDK5 in an effort to achieve improved protection against hypoxia. Finally, o
