First oral GLI1 PROTAC takes aim at colorectal cancer
- Targets GLI1, the Hedgehog effector downstream of SMO, to reach tumors resistant to SMO inhibitors, using a new series of CRBN-recruiting PROTAC degraders.
- Lead LRG20 degrades GLI1 and GLI2 more than GLI3 in HT-29 colorectal cells, via the ubiquitin-proteasome system, sparing typical CRBN neo-substrates.
- It suppresses cell growth, shows oral exposure in vivo, and curbs HT-29 xenograft tumors without evident toxicity.
💡 Points Based on the abstract
A transcription factor with no pocket is a classic degrader use case, and sparing the usual CRBN neo-substrates is reassuring. But GLI1/GLI2 preference over GLI3 needs proteome-wide support, and I'd want a non-degrading CRBN-binder control to prove the effect isn't just pathway noise. Next check: activity in SMO-inhibitor-resistant models, plus ternary-complex cooperativity, since oral exposure for a large PROTAC is the real surprise.
Discovery of the first orally bioavailable GLI1 PROTAC for the treatment of colorectal cancer ↗