Identification, characterization, and implications of species-dependent plasma protein binding for the oral Hedgehog pathway inhibitor vismodegib (GDC-0449).
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Giannetti AM, Wong H, Dijkgraaf GJ, Dueber EC, Ortwine DF, Bravo BJ, Gould SE, Plise EG, Lum BL, Malhi V, Graham RA
Identification, characterization, and implications of species-dependent plasma protein binding for the oral Hedgehog pathway inhibitor vismodegib (GDC-0449).
J Med Chem. 2011 Apr 28;54(8):2592-601. doi: 10.1021/jm1008924. Epub 2011 Mar 25.
- PubMed ID
- 21438527 [ View in PubMed]
- Abstract
Vismodegib (GDC-0449) is is an orally available selective Hedgehog pathway inhibitor in development for cancer treatment. The drug is >/=95% protein bound in plasma at clinically relevant concentrations and has an approximately 200-fold longer single dose half-life in humans than rats. We have identified a strong linear relationship between plasma drug concentrations and alpha-1-acid glycoprotein (AAG) in a phase I study. Biophysical and cellular techniques have been used to reveal that vismodegib strongly binds to human AAG (K(D) = 13 muM) and binds albumin with lower affinity (K(D) = 120 muM). Additionally, binding to rat AAG is reduced approximately 20-fold relative to human, whereas the binding affinity to rat and human albumin was similar. Molecular docking studies reveal the reason for the signficiant species dependence on binding. These data highlight the utility of biophysical techniques in creating a comprehensive picture of protein binding across species.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Vismodegib Serum albumin Kd (nM) 1.30E+05 N/A N/A Details Vismodegib Serum albumin Kd (nM) 5.50E+03 N/A N/A Details Vismodegib Serum albumin Kd (nM) 6.00E+03 N/A N/A Details Vismodegib Serum albumin Kd (nM) 1.20E+05 N/A N/A Details Warfarin Serum albumin Kd (nM) 5.10E+05 N/A N/A Details Warfarin Serum albumin Kd (nM) 5.40E+03 N/A N/A Details Warfarin Serum albumin Kd (nM) 2.00E+03 N/A N/A Details Warfarin Serum albumin Kd (nM) 1.20E+04 N/A N/A Details