Discovery of Dual MER/AXL Kinase Inhibitors as Bifunctional Small Molecules for Inhibiting Tumor Growth and Enhancing Tumor Immune Microenvironment

A series of bifunctional
compounds have been discovered for their
dual functionality as MER/AXL inhibitors and immune modulators. The
furanopyrimidine scaffold, renowned for its suitability in kinase
inhibitor discovery, offers at least three distinct pharmacophore
access points. Insights from molecular modeling studies guided hit-to-lead
optimization, which revealed that the 1,3-diketone side chain hybridized
with furanopyrimidine scaffold that respectively combined amino-type
substituent and 1H-pyrazol-4-yl substituent on the
top and bottom of the aryl regions to produce 22 and 33, exhibiting potent antitumor activities in various syngeneic
and xenograft models. More importantly, 33 demonstrated
remarkable immune-modulating activity by upregulating the expression
of total T-cells, cytotoxic CD8+ T-cells, and helper CD4+ T-cells in the spleen. These findings underscored the bifunctional
capabilities of 33 (BPR5K230) with excellent
oral bioavailability (F = 54.6%), inhibiting both
MER and AXL while modulating the tumor microenvironment and highlighting
its diverse applicability for further studies to advance its therapeutic
potential.