title: A simple method for predicting serum protein binding of compounds from IC(50) shift analysis for in vitro assays.
abstract: The shift in apparent IC(50) that attends addition of serum proteins to in vitro cellular, enzymatic, and receptor binding assays can be used to determine the dissociation constant for compound-serum protein complexes. We show here that a simple linear relationship exists between the apparent IC(50) in the presence of serum protein and the inverse of the apparent K(d) for the compound-serum protein complex. Using a series of cell-active kinase inhibitors we demonstrate that the K(d) value derived in this way can be used to predict the extent of protein binding in serum for various compounds. This method should provide a simple means of assessing the relative serum protein binding propensity of compounds early in the compound optimization phase of drug discovery campaigns.
authors.affiliation: GlaxoSmithKline, Department of Oncology Biology, Research Triangle Park, NC 27709, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Rusnak
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Lai
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Lansing
authors.forename: Nelson
authors.initials: N
authors.lastname: Rhodes
authors.forename: Tona M
authors.initials: TM
authors.lastname: Gilmer
authors.forename: Robert A
authors.initials: RA
authors.lastname: Copeland
mesh_terms: D001798:Blood Proteins / Q000378:metabolism*; D066298:In Vitro Techniques; D011485:Protein Binding
chemical_list: D001798:Blood Proteins