title: Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry.
abstract: Interactions between kinases and small molecule inhibitors can be activation state dependent. A detailed understanding of inhibitor binding therefore requires characterizing interactions across multiple activation states. We have systematically explored the effects of ABL1 activation loop phosphorylation and PDGFR family autoinhibitory juxtamembrane domain docking on inhibitor binding affinity. For a diverse compound set, the affinity patterns correctly classify inhibitors as having type I or type II binding modes, and we show that juxtamembrane domain docking can have dramatic negative effects on inhibitor affinity. The results have allowed us to associate ligand-induced conformational changes observed in cocrystal structures with specific energetic costs. The approach we describe enables investigation of the complex relationship between kinase activation state and compound binding affinity and should facilitate strategic inhibitor design.
authors.affiliation: Ambit Biosciences, 4215 Sorrento Valley Boulevard, San Diego, CA 92121, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Wodicka
authors.forename: Pietro
authors.initials: P
authors.lastname: Ciceri
authors.forename: Mindy I
authors.initials: MI
authors.lastname: Davis
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Hunt
authors.forename: Mark
authors.initials: M
authors.lastname: Floyd
authors.forename: Sara
authors.initials: S
authors.lastname: Salerno
authors.forename: Xuequn H
authors.initials: XH
authors.lastname: Hua
authors.forename: Julia M
authors.initials: JM
authors.lastname: Ford
authors.forename: Robert C
authors.initials: RC
authors.lastname: Armstrong
authors.forename: Patrick P
authors.initials: PP
authors.lastname: Zarrinkar
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Treiber
mesh_terms: D000595:Amino Acid Sequence; D003198:Computer Simulation; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000737:chemistry / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D019009:Proto-Oncogene Proteins c-kit; D016186:Receptor, Macrophage Colony-Stimulating Factor; D020797:Receptor, Platelet-Derived Growth Factor beta; D051941:fms-Like Tyrosine Kinase 3; D016315:Proto-Oncogene Proteins c-abl