ERIC 2024 | Targeting B-cell receptor signaling with BTK degraders to treat CLL

BTK degraders are another way to target one of the pillars of B-cell receptor signaling, that is this kinase, Brutons tyrosine kinase, in a different way from the conventional approach. The conventional approach was to have molecules that covalently or non-covalently bind to BTK, inhibiting its activation, inhibiting its phosphorylation. With BTK inhibitors it turns out that quite often there are mechanisms of resistance that are coming up. One of them again is mutations of the target but also there are pathways that get activated when the signaling is strong in which there is a bypass of the signaling outside the BTK associated pathway. So the way BTK degraders instead want to operate is by degrading the full molecule which has two results mainly. One BTK is not there so it’s not susceptible to mutations. You remove the molecule itself. The second is that BTK is part of a big scaffold with associated or non-associated pathway linked to this scaffold. So that if you remove the degrader you may actually remove the alternative pathways that can bypass BTK. So it has this dual role and there are now several BTK degraders. In Southampton we have had the experience to use the Nurix degrader and this is giving very nice results and hopefully we will be able to use them alone or more likely in combination with other drugs. Thank you.