The discovery of small-molecule inhibitors of cFLIP that sensitise tumour cells to TNF-related apoptosis-inducing ligand

The TNF-related apoptosis-inducing ligand (TRAIL) has potential as a therapeutic agent, as it has previously been shown to induce apoptosis in triple-negative breast cancer. However, several studies have demonstrated that patients with tumours develop resistance to TRAIL. We have previously shown that suppression of the TRAIL-receptor inhibitor cFLIP can sensitise breast cancer stem cells to apoptosis inducers, but development of inhibitors of cFLIP have been impeded by concerns over structural similarities between cFLIP and the pro-apoptotic procaspase-8. In this work, we used an in silico approach that led to the identification of a hit compound that selectively inhibits cFLIP binding to the DISC and promoted TRAIL-mediated apoptosis in breast cancer cell lines. We also carried out a hit-expansion programme to derive the structure–activity relationships of this chemical scaffold. Our findings confirm the proof of principle that selective inhibition of cFLIP can be used to target a vulnerability in breast cancer cells.