Structure-based drug design enables conversion of a DFG-in binding CSF-1R kinase inhibitor to a DFG-out binding mode.
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.
Meyers
Marvin J
MJ
Pfizer Global Research & Development, St. Louis Laboratories, 700 Chesterfield Parkway West, Chesterfield, MO 63017, United States. marvin.j.meyers@pfizer.com
Pelc
Matthew
M
Kamtekar
Satwik
S
Day
Jacqueline
J
Poda
Gennadiy I
GI
Hall
Molly K
MK
Michener
Marshall L
ML
Reitz
Beverly A
BA
Mathis
Karl J
KJ
Pierce
Betsy S
BS
Parikh
Mihir D
MD
Mischke
Deborah A
DA
Long
Scott A
SA
Parlow
John J
JJ
Anderson
David R
DR
Thorarensen
Atli
A
D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D057166:High-Throughput Screening Assays; D006860:Hydrogen Bonding; D008968:Molecular Conformation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism
D047428:Protein Kinase Inhibitors; D016186:Receptor, Macrophage Colony-Stimulating Factor