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.
Pfizer Global Research & Development, St. Louis Laboratories, 700 Chesterfield Parkway West, Chesterfield, MO 63017, United States. marvin.j.meyers@pfizer.com
Marvin J
MJ
Meyers
Matthew
M
Pelc
Satwik
S
Kamtekar
Jacqueline
J
Day
Gennadiy I
GI
Poda
Molly K
MK
Hall
Marshall L
ML
Michener
Beverly A
BA
Reitz
Karl J
KJ
Mathis
Betsy S
BS
Pierce
Mihir D
MD
Parikh
Deborah A
DA
Mischke
Scott A
SA
Long
John J
JJ
Parlow
David R
DR
Anderson
Atli
A
Thorarensen
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