Colony-stimulating
factor-1 receptor (CSF1R) is implicated in tumor-associated
macrophage (TAM) repolarization and has emerged as a promising target
for cancer immunotherapy. Herein, we describe the discovery of orally
active and selective CSF1R inhibitors by property-driven optimization
of BPR1K871 (9), our clinical multitargeting kinase inhibitor.
Molecular docking revealed an additional nonclassical hydrogen-bonding
(NCHB) interaction between the unique 7-aminoquinazoline scaffold
and the CSF1R hinge region, contributing to CSF1R potency enhancement.
Structural studies of CSF1R and Aurora kinase B (AURB) demonstrated
the differences in their back pockets, which inspired the use of a
chain extension strategy to diminish the AURA/B activities. A lead
compound BPR1R024 (12) exhibited potent CSF1R activity
(IC50 = 0.53 nM) and specifically inhibited protumor M2-like
macrophage survival with a minimal effect on antitumor M1-like macrophage
growth. In vivo, oral administration of 12 mesylate delayed the MC38 murine colon tumor growth and reversed
the immunosuppressive tumor microenvironment with the increased M1/M2
ratio.
With the demands of the high-throughput assay of biomarkers
of
ultralow concentrations in clinics, a 36-channel instrument utilizing
immunomagnetic reduction (IMR) has been developed. The instrument
involves the use of a high-T
c superconducting-quantum-interference-device
(SQUID) magnetometer to detect the signals due to the associations
between target biomarker molecules and the antibody-functionalized
magnetic nanoparticles in the reagent of IMR. In addition to illustrating
the design and the measurements of the instrument, the assay characterizations
for eight kinds of biomarkers related to neurodegenerative disease
are investigated. Furthermore, the assay results among three independent
instruments were compared. For an instrument, the channel-to-channel
variations in measured concentrations of biomarkers are within a range
of 2.09 to 5.62%. The assay accuracy was found to be from 99 to 103.7%.
The p values in measured concentrations for any of
the tested biomarkers were higher than 0.05 among the three instruments.
The results demonstrate high throughput, high stability, and high
consistency for the SQUID-IMR instruments.
Antibody-functionalized magnetic nanoparticles dispersed in phosphate-buffered saline solution were used as reagents in immunomagnetic reduction assays. Biomolecules are detected in bioliquid samples when they associate with magnetic nanoparticles and reduce the AC magnetic susceptibility χac of the reagent at a given frequency. In this study, the chemical kinetics for the real-time χac during the association was investigated. The association kinetics between biomolecules and nanoparticles consists of diffusion and binding steps. It was found that the diffusion speeds up in samples with higher concentrations of molecules. Furthermore, the period of association was longer for samples having higher concentrations of molecules. The association rates were proportional to the T-Tau concentration. The results showed that one biomolecule was associated with one magnetic nanoparticle.
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