Structure-based drug design enables conversion of a DFG-in binding CSF-1R kinase inhibitor to a DFG-out binding mode

Marvin J Meyers; Matthew Pelc; Satwik Kamtekar; Jacqueline Day; Gennadiy I Poda; Molly K Hall; Marshall L Michener; Beverly A Reitz; Karl J Mathis; Betsy S Pierce; Mihir D Parikh; Deborah A Mischke; Scott A Long; John J Parlow; David R Anderson; Atli Thorarensen

doi:10.1016/j.bmcl.2010.01.078

Structure-based drug design enables conversion of a DFG-in binding CSF-1R kinase inhibitor to a DFG-out binding mode

Bioorg Med Chem Lett. 2010 Mar 1;20(5):1543-7. doi: 10.1016/j.bmcl.2010.01.078. Epub 2010 Jan 21.

Authors

Marvin J Meyers¹, Matthew Pelc, Satwik Kamtekar, Jacqueline Day, Gennadiy I Poda, Molly K Hall, Marshall L Michener, Beverly A Reitz, Karl J Mathis, Betsy S Pierce, Mihir D Parikh, Deborah A Mischke, Scott A Long, John J Parlow, David R Anderson, Atli Thorarensen

Affiliation

¹ Pfizer Global Research & Development, St. Louis Laboratories, 700 Chesterfield Parkway West, Chesterfield, MO 63017, United States. [email protected]

PMID: 20137931
DOI: 10.1016/j.bmcl.2010.01.078

Abstract

The work described herein demonstrates the utility of structure-based drug design (SBDD) in shifting the binding mode of an HTS hit from a DFG-in to a DFG-out binding mode resulting in a class of novel potent CSF-1R kinase inhibitors suitable for lead development.

MeSH terms

Binding Sites
Crystallography, X-Ray
Drug Design
High-Throughput Screening Assays
Hydrogen Bonding
Molecular Conformation
Protein Binding
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology
Receptor, Macrophage Colony-Stimulating Factor / antagonists & inhibitors*
Receptor, Macrophage Colony-Stimulating Factor / metabolism

Substances

Protein Kinase Inhibitors
Receptor, Macrophage Colony-Stimulating Factor