iwCLL 2023 | Using BTK degraders as a treatment strategy for patients with CLL
Francesco Forconi, MD, DM, PhD, FRCPath, University of Southampton, Southampton, UK, discusses the use of BTK degraders as a treatment strategy for patients with chronic lymphocytic leukemia (CLL) and outlines the molecular mechanisms underlying their functionality. Prof. Forconi elaborates on the BTK degraders currently in Phase I trials. This interview took place at the 20th International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Biennial Meeting, held in Boston, MA.
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Transcript (edited for clarity)
BTK degraders is really a very interesting and quite attractive approach into targeting BCR inhibitors. Degradation of molecules that are expected to be fundamental to the pathogenesis of individual tumors is taking a lot of space in the therapeutics of different cancers. In the case of CLL, BTK degraders are one of these approaches. So the way by which BTK degradation operates is by use of these compounds, these small molecules, that are able to recruit the cereblon E3 ubiquitin ligase complex bringing it to the BTK molecule, so this gets ubiquitinated and eventually degraded...
BTK degraders is really a very interesting and quite attractive approach into targeting BCR inhibitors. Degradation of molecules that are expected to be fundamental to the pathogenesis of individual tumors is taking a lot of space in the therapeutics of different cancers. In the case of CLL, BTK degraders are one of these approaches. So the way by which BTK degradation operates is by use of these compounds, these small molecules, that are able to recruit the cereblon E3 ubiquitin ligase complex bringing it to the BTK molecule, so this gets ubiquitinated and eventually degraded. So what is missing is not the activity of the kinase by inhibition of phosphorylation, but it really is the total degradation of that specific molecule.
So expectedly there are a couple of actions that happen. One, the molecule is not susceptible to mutations, of course, it’s not there anymore. So the action won’t be there. The other important thing is that it may operate by destroying the scaffold, letting the scaffold of the kinase complex of the kinases and proteins recruited upon B-cell receptor signaling activation at the membrane, so that the pathways should all be inhibited.
There are several BTK degraders that are being brought in Phase I trials. We have had the opportunity of using one of these in a Phase I trial for all B-cell malignancies, including CLL. This is the NX-5948 Bruton tyrosine kinase degrader by Nurix, and we are putting a lot of hopes in the activity of this drug and its efficacy. The trial is in its Phase I dose escalation. And we hope after this introduction at the iwCLL 2023 conference, we hope to deliver the first results related to its toxicity in particular, or safety, I would say, at the American Society of Hematology conference in December.
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