Long-Acting Tumor-Activated Prodrug of a TGFβR Inhibitor

Inhibition of TGFβ signaling
in concert with a checkpoint
blockade has been shown to provide improved and durable antitumor
immune response in mouse models. However, on-target adverse cardiovascular
effects have limited the clinical use of TGFβ receptor (TGFβR)
inhibitors in cancer therapy. To restrict the activity of TGFβR
inhibitors to tumor tissues and thereby widen the therapeutic index,
a series of tumor-activated prodrugs of a selective small molecule
TGFβR1 inhibitor 1 were prepared by appending 1 to a serine protease substrate and a half-life extension
fatty acid carbon chain. The prodrugs were shown to be selectively
metabolized in tumor tissues relative to the heart and blood and demonstrated
a prolonged favorable increase in the tumor-to-heart ratio of the
active drug in tissue distribution studies. Once-weekly administration
of the most tissue-selective compound 10 provided anti-tumor
efficacy comparable to the parent compound and reduced systemic exposure
of the active drug.