Discovery of 4-aminoquinolines as highly selective TGFβR1 inhibitors with an attenuated MAP4K4 profile for potential applications in immuno-oncology.

Abstract The tumor microenvironment contains high concentrations of TGFβ, a crucial immunosuppressive cytokine. TGFβ stimulates immune escape by promoting peripheral immune tolerance to avoid tumoricidal attack. Small-molecule inhibitors of TGFβR1 are a prospective method for next-generation immunotherapies. In the present study, we identified selective 4-aminoquinoline-based inhibitors of TGFβR1 through structural and rational-based design strategies. This led to the identification of compound 4i, which was found to be selective for TGFβR1 with the exception of MAP4K4 in the kinase profiling assay. The compound was then further optimized to remove MAP4K4 activity, since MAP4K4 is vital for proper T-cell function and its inhibition could exacerbate tumor immunosuppression. Optimization efforts led to compound 4s that inhibited TGFβR1 at an IC50 of 0.79 ± 0.19 nM with 2000-fold selectivity against MAP4K4. Compound 4s represents a highly selective TGFβR1 inhibitor that has potential applications in immuno-oncology.