Home Blog of Signal Transduction Cell Cycle PLK Unusually High Affinity of the PLK Inhibitors RO3280 and GSK461364 to HSA and Its Possible Pharmacokinetic Implications

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Unusually High Affinity of the PLK Inhibitors RO3280 and GSK461364 to HSA and Its Possible Pharmacokinetic Implications

The binding processes of two Polo-like kinase inhibitors, RO3280 and GSK461364, to the human serum albumin (HSA) protein as well as the protonation equilibria of both compounds have been studied combining absorbance and fluorescence spectroscopy experiments together with density functional theory calculations. We found that the charge states of RO3280 and GSK461364 are +2 and +1, respectively, at the physiological pH. Nevertheless, RO3280 binds to HSA in the charge state +1 prior to a deprotonation pre-equilibrium. Binding constants to site I of HSA of 2.23 × 106 and 8.80 × 104 M-1 were determined for RO3280 and GSK461364, respectively, at 310 K. The binding processes of RO3280 and GSK461364 to HSA are entropy- and enthalpy-driven, respectively. The positive enthalpy found for the RO3280-HSA complex formation could be related to a proton pre-equilibrium of RO3280.

 

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The study investigated the binding processes of two Polo-like kinase inhibitors, RO3280 and GSK461364, to the human serum albumin (HSA) protein. The researchers used absorbance and fluorescence spectroscopy experiments and density functional theory calculations to understand the protonation equilibria of both compounds.

The study found that at physiological pH, RO3280 and GSK461364 had charge states of +2 and +1, respectively. However, RO3280 bound to HSA in the charge state +1 before undergoing a deprotonation pre-equilibrium. The researchers determined binding constants of 2.23 × 106 and 8.80 × 104 M-1 for RO3280 and GSK461364, respectively, at 310 K, indicating a higher binding affinity of RO3280 for HSA.

The binding processes of RO3280 and GSK461364 to HSA were found to be entropy- and enthalpy-driven, respectively. The positive enthalpy found for the RO3280-HSA complex formation could be related to a proton pre-equilibrium of RO3280, indicating that the binding process involved a change in the protonation state of the compound.

Overall, the study provides important insights into the binding processes of RO3280 and GSK461364 to HSA, which can have implications for the development of novel therapeutics targeting Polo-like kinase.

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Cat.No. Product Name Information
S2193 GSK461364 GSK461364 (GSK461364A) inhibits purified Plk1 with Ki of 2.2 nM in a cell-free assay. It is more than 1000-fold selective against Plk2/3.

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PLK