Amide conjugates of ketoprofen and indole as inhibitors of Gli1-mediated transcription in the Hedgehog pathway.

We have previously reported small-molecule inhibitors of Gli1-mediated transcription, an essential down-stream element of the Hh pathway. We created new derivatives of the previous compounds aiming to improve the druggable properties. The new compounds, amide conjugates of ketoprofen and indole, showed inhibitory activity and membrane permeability, while also improving the microsome stability. Among them, 33 and 42 inhibited Gli-luciferase reporter in C3H10T1/2 cells that were exogenously transfected with Gli1 with 2.6 μM and 1.6 μM of IC₅₀, respectively, and in Rh30 cells that endogenously overexpress Gli1, and were selective to Gli1 over Gli2.