8CGC

Structure of CSF1R in complex with a pyrollopyrimidine (compound 23)

Summary for 8CGC

• Entry DOI: 10.2210/pdb8cgc/pdb
• Descriptor: Macrophage colony-stimulating factor 1 receptor, (2S)-2-hydroxybutanedioic acid, GLYCEROL, ... (5 entities in total)
• Functional Keywords: kinase, csf1r, inhibitors, ligase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 39244.94

Authors

Aarhus, T.I.,Bjornstad, F.,Wolowczyk, C.,Larsen, K.U.,Rognstad, L.,Leithaug, T.,Unger, A.,Habenberger, P.,Wolff, A.,Bjorkoy, G.,Pridans, C.,Eickhoff, J.,Klebl, B.,Hoff, B.H.,Sundby, E. (deposition date: 2023-02-03, release date: 2023-05-24, Last modification date: 2024-02-07)

Primary citation

Aarhus, T.I.,Bjornstad, F.,Wolowczyk, C.,Larsen, K.U.,Rognstad, L.,Leithaug, T.,Unger, A.,Habenberger, P.,Wolf, A.,Bjorkoy, G.,Pridans, C.,Eickhoff, J.,Klebl, B.,Hoff, B.H.,Sundby, E.
Synthesis and Development of Highly Selective Pyrrolo[2,3- d ]pyrimidine CSF1R Inhibitors Targeting the Autoinhibited Form.
J.Med.Chem., 66:6959-6980, 2023

PubMed Abstract: Colony-stimulating factor-1 receptor (CSF1R) is a receptor tyrosine kinase that controls the differentiation and maintenance of most tissue-resident macrophages, and the inhibition of CSF1R has been suggested as a possible therapy for a range of human disorders. Herein, we present the synthesis, development, and structure-activity relationship of a series of highly selective pyrrolo[2,3-]pyrimidines, showing subnanomolar enzymatic inhibition of this receptor and with excellent selectivity toward other kinases in the platelet-derived growth factor receptor (PDGFR) family. The crystal structure of the protein and revealed that the binding conformation of the protein is DFG-out-like. The most promising compounds in this series were profiled for cellular potency and subjected to pharmacokinetic profiling and stability, indicating that this compound class could be relevant in a potential disease setting. Additionally, these compounds inhibited primarily the autoinhibited form of the receptor, contrasting the behavior of pexidartinib, which could explain the exquisite selectivity of these structures.

PubMed: 37191268
DOI: 10.1021/acs.jmedchem.3c00428

Experimental method

X-RAY DIFFRACTION (1.925 Å)