PP2A-δ Inhibitors

Chemical inhibitors of PP2A-δ can act through a variety of mechanisms to impede its role in dephosphorylation of proteins. Okadaic Acid, for example, is a potent inhibitor that achieves this by binding directly to the catalytic subunit of PP2A-δ, which is essential for its activity. This binding prevents PP2A-δ from interacting with its substrates, thereby maintaining proteins in a phosphorylated state. Similarly, Calyculin A inhibits PP2A-δ by interacting with its catalytic site, blocking enzymatic activity. Cantharidin also binds covalently to the catalytic subunit of PP2A-δ, providing another example of a direct inhibitor that prevents the dephosphorylation process essential to PP2A-δ's function. Endothall contributes to this inhibitory effect by mimicking the transition state of dephosphorylation and blocking substrate access to the active site of PP2A-δ.

In addition to these direct inhibitors, other chemicals like Ionomycin can indirectly inhibit PP2A-δ by increasing intracellular calcium levels, which in turn can affect the regulatory B subunits that are part of PP2A-δ's regulatory mechanism. Demecolcine disrupts microtubule polymerization, which in turn can influence PP2A-δ signaling pathways that are critical for cell cycle control. By disrupting these pathways, Demecolcine can indirectly lead to inhibition of PP2A-δ's function. Fostriecin, Tautomycin, and Microcystin-LR are other examples that target the active site of PP2A-δ, binding directly to impede its phosphatase activity. This is also seen with Phenylarsine Oxide, which interferes with the catalytic function by interacting with vicinal dithiols within the catalytic subunit of PP2A-δ. Nodularin and Cylindrospermopsin inhibit PP2A-δ in a manner similar to Okadaic Acid and Microcystin-LR, by binding to the active site and preventing the dephosphorylation of proteins, leading to the functional inhibition of the PP2A-δ protein itself. These diverse yet specific chemical interactions collectively contribute to the functional inhibition of PP2A-δ, each affecting the protein's activity through a unique biochemical interaction or cellular process.