Discovery of pyrazolopyrimidines that selectively inhibit CSF-1R kinase by iterative design, synthesis and screening against glioblastoma cells

Glioblastoma multiforme (GBM) is the most aggressive type of brain cancer in adults, with an average life expectancy under treatment of approx. 15 months. GBM is characterised by a complex set of genetic alterations that results in significant disruption of receptor tyrosine kinase (RTK) signaling....

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Bibliographic Details
Published in:MedChemComm 2023-12, Vol.14 (12), p.2611-2624
Main Authors: Baillache, Daniel J, Valero, Teresa, Lorente-Macías, Álvaro, Bennett, David Jonathan, Elliott, Richard J. R, Carragher, Neil O, Unciti-Broceta, Asier
Format: Article
Language:English
Subjects:
Antiproliferatives
Brain cancer
Cancer
Cerebrospinal fluid
Chemistry
Colony-stimulating factor
Glioblastoma
Glioblastoma cells
Glioma cells
Immunoregulation
Kinases
Life expectancy
Life span
Microenvironments
Protein-tyrosine kinase receptors
Receptors
Stem cells
Synthesis
Tumorigenesis
Tyrosine
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Summary:Glioblastoma multiforme (GBM) is the most aggressive type of brain cancer in adults, with an average life expectancy under treatment of approx. 15 months. GBM is characterised by a complex set of genetic alterations that results in significant disruption of receptor tyrosine kinase (RTK) signaling. We report here an exploration of the pyrazolo[3,4- d ]pyrimidine scaffold in search for antiproliferative compounds directed to GBM treatment. Small compound libraries were synthesised and screened against GBM cells to build up structure-antiproliferative activity-relationships (SAARs) and inform further rounds of design, synthesis and screening. 76 novel compounds were generated through this iterative process that found low micromolar potencies against selected GBM lines, including patient-derived stem cells. Phenomics analysis demonstrated preferential activity against glioma cells of the mesenchymal subtype, whereas kinome screening identified colony stimulating factor-1 receptor (CSF-1R) as the lead's target, a RTK implicated in the tumourigenesis and progression of different cancers and the immunoregulation of the GBM microenvironment. Compound libraries synthesised and screened against glioma cells built up structure-antiproliferative activity-relationships and informed further design, synthesis and screening, resulting in the discovery of potent CSF-1R inhibitors.
ISSN:2632-8682
2040-2503
2632-8682
2040-2511
DOI:10.1039/d3md00454f