학술논문
Discovery of pyrazolopyrimidines that selectively inhibit CSF-1R kinase by iterative design, synthesis and screening against glioblastoma cellsElectronic supplementary information (ESI) available: Methods, characterisation of intermediates and final compounds, NMR spectra of compounds B40–63, Table S1 and Fig. S1–S11. See DOI: https://doi.org/10.1039/d3md00454f
Document Type
Article
Author
Source
MedChemComm; 2023, Vol. 14 Issue: 12 p2611-2624, 14p
Subject
Language
ISSN
20402503; 20402511
Abstract
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.