Discovery of pyrazolopyrimidines that selectively inhibit CSF-1R kinase by iterative design, synthesis and screening against glioblastoma cells.
Daniel J BaillacheTeresa ValeroÁlvaro Lorente-MacíasDavid Jonathan BennettRichard J R ElliottNeil O CarragherAsier Unciti-BrocetaPublished in: RSC medicinal chemistry (2023)
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.
Keyphrases
- tyrosine kinase
- stem cells
- induced apoptosis
- cell cycle arrest
- epidermal growth factor receptor
- small molecule
- squamous cell carcinoma
- genome wide
- gene expression
- magnetic resonance imaging
- papillary thyroid
- image quality
- computed tomography
- high throughput
- resting state
- multiple sclerosis
- functional connectivity
- subarachnoid hemorrhage
- pi k akt
- cerebral ischemia
- dual energy