Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry

Lisa M Wodicka; Pietro Ciceri; Mindy I Davis; Jeremy P Hunt; Mark Floyd; Sara Salerno; Xuequn H Hua; Julia M Ford; Robert C Armstrong; Patrick P Zarrinkar; Daniel K Treiber

doi:10.1016/j.chembiol.2010.09.010

Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry

Chem Biol. 2010 Nov 24;17(11):1241-9. doi: 10.1016/j.chembiol.2010.09.010.

Authors

Lisa M Wodicka¹, Pietro Ciceri, Mindy I Davis, Jeremy P Hunt, Mark Floyd, Sara Salerno, Xuequn H Hua, Julia M Ford, Robert C Armstrong, Patrick P Zarrinkar, Daniel K Treiber

Affiliation

¹ Ambit Biosciences, 4215 Sorrento Valley Boulevard, San Diego, CA 92121, USA.

PMID: 21095574
DOI: 10.1016/j.chembiol.2010.09.010

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.

MeSH terms

Amino Acid Sequence
Computer Simulation
Molecular Sequence Data
Phosphorylation
Protein Binding
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology
Protein Structure, Tertiary
Proto-Oncogene Proteins c-abl / antagonists & inhibitors*
Proto-Oncogene Proteins c-abl / metabolism
Proto-Oncogene Proteins c-kit / antagonists & inhibitors
Proto-Oncogene Proteins c-kit / metabolism
Receptor, Macrophage Colony-Stimulating Factor / antagonists & inhibitors
Receptor, Macrophage Colony-Stimulating Factor / metabolism
Receptor, Platelet-Derived Growth Factor beta / chemistry
Receptor, Platelet-Derived Growth Factor beta / metabolism
Small Molecule Libraries / chemistry*
Small Molecule Libraries / pharmacology
fms-Like Tyrosine Kinase 3 / antagonists & inhibitors
fms-Like Tyrosine Kinase 3 / metabolism

Substances

Protein Kinase Inhibitors
Small Molecule Libraries
Proto-Oncogene Proteins c-kit
Receptor, Macrophage Colony-Stimulating Factor
Receptor, Platelet-Derived Growth Factor beta
fms-Like Tyrosine Kinase 3
Proto-Oncogene Proteins c-abl