Discovery of BPR1R024, an Orally Active and Selective CSF1R Inhibitor that Exhibits Antitumor and Immunomodulatory Activity in a Murine Colon Tumor Model

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.