iwCLL 2025 | Targeted degradation of NF-κB RelA/p65 using a PBD-based PROTAC: a novel therapeutic strategy in CLL

Well, we’ve developed a completely new type of drug strategy for CLL. So this type of strategy completely eliminates the protein that we’re going after rather than just inhibiting it. And why is that important? Well, because sometimes when you use small molecule inhibitors, when that small molecule inhibitor floats off its protein target, that protein can do its job again. And so patients have to keep getting dosed repeatedly in order to maintain the effect on the protein target. This strategy literally latches onto that protein of interest and uses the cell’s own machinery called the proteasome, but it’s like a recycling bin, to actually push that protein and destroy it in that particular part of the cell. So we went after a particular protein called RelA/p65, and this is part of the NF-kappa-B family of proteins. And that’s really important because all CLL patients have high levels of NF-kappa-B because of either mutations that they’ve acquired that cause the activation of NF-kappa B or through microenvironmental signalling. So we’re really excited about this drug. It’s the first in class. No one’s ever managed to make a selective RelA inhibitor before, let alone a PROTAC. And we presented the data at the meeting here yesterday. And yeah, I think it went down really well because people are genuinely interested about this as a particular type of drug strategy. 

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