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Discovery of Pyrrolo[2,3-d]pyrimidine derivatives as potent and selective colony stimulating factor 1 receptor kinase inhibitors.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2022 Dec 05; Vol. 243, pp. 114782. Date of Electronic Publication: 2022 Sep 21. - Publication Year :
- 2022
-
Abstract
- Colony stimulating factor 1 receptor kinase (CSF1R) plays an integral role in tumor-associated macrophage repolarization and has emerged as a novel therapeutic target for cancer immunotherapy. Most of the current CSF1R kinase inhibitors lack selectivity between CSF1R kinase and other type III growth factor receptor members. Herein, we report a potent and selective CSF1R inhibitor 18h, which displays an IC <subscript>50</subscript> value of 5.14 nM against CSF1R and achieves selectivity over other type III receptor tyrosine kinases (>38-fold). 18h inhibits the phosphorylation of CSF1R and its downstream signaling pathway in RAW264.7, THP-1, and M-NFS-60 cells. Treatment with this compound leads to alteration of the macrophage polarization in RAW264.7 macrophages in a dose-dependent manner. In vivo, 18h demonstrates acceptable pharmacokinetic profiles and suppresses the tumor growth in a mouse xenograft model inoculated with M-NFS-60 cells.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Humans
Mice
Animals
Macrophage Colony-Stimulating Factor metabolism
Protein Kinase Inhibitors pharmacology
Receptor Protein-Tyrosine Kinases
Receptors, Colony-Stimulating Factor
Pyrimidines pharmacokinetics
Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
Antineoplastic Agents therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 243
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 36179404
- Full Text :
- https://doi.org/10.1016/j.ejmech.2022.114782