PASK Inhibitors

Chemical inhibitors of PASK can be diverse in their mechanisms of action, each targeting the kinase in different ways to achieve inhibition. Staurosporine is a well-known kinase inhibitor that acts by occupying the ATP binding site of PASK, which is essential for its kinase activity. This competitive inhibition prevents PASK from phosphorylating its substrates, leading to a functional inhibition of its activity. Similarly, H-89 targets the ATP binding site of PASK, acting as a competitor and thereby hindering the enzyme's catalytic action. The inhibition is also observed with 5-Iodotubercidin, which, by competing with ATP, can block the phosphorylating action PASK is supposed to carry out. K252a, another kinase inhibitor, binds to the same site and prevents ATP from engaging with PASK, ensuring that the kinase cannot exert its normal function.

Furthermore, compounds like Indirubin-3'-monoxime and Roscovitine disrupt the kinase activity of PASK by preventing ATP from binding to its active site, which is a crucial step for the kinase to function. SP600125, although primarily a JNK inhibitor, can also inhibit PASK by blocking the ATP binding domain, thereby preventing activation. SB 203580 and PD 98059 exert their inhibitory effects on PASK by interfering with the phosphorylation process, which is a critical activity that PASK performs. LY294002 and Wortmannin target the PI3K/AKT pathway, which is indirectly related to PASK's regulatory functions. By inhibiting PI3K, these compounds reduce the downstream signaling events that would otherwise contribute to PASK activation. Rapamycin, an mTOR inhibitor, disrupts the nutrient and energy sensing pathway, which is intimately connected to the regulatory functions of PASK, leading to a decrease in PASK activity as part of the broader inhibition of the pathway.