A reversible, non-covalent Bruton’s tyrosine kinase epi-inhibitor for B-cell malignancies: preclinical study

Chronic lymphocytic leukemia (CLL) can be a therapeutic challenge. Notwithstanding substantial progress in therapeutic approaches with small molecule inhibitors, the emergence of inhibitor resistance and suboptimal long-term outcomes highlight the persistent need for novel, more effective treatment strategies. A preclinical study at the University of Campania (Naples, Italy) evaluated the novel tyrosine kinase inhibitory activity of UVI5008, currently the only known epigenetic modulator that directly targets Bruton’s tyrosine kinase (BTK), affecting both BTK expression and enzymatic function. Combined in silico, ex vivo, and in vivo analyses revealed that UVI5008 effectively inhibits both wild-type BTK and the C418S mutated BTK isoform, commonly associated with BTK-inhibitor resistance in CLL. In B-cell lymphoma and leukemia models, UVI5008 led to a substantial increase in cellular apoptosis, reduction of phosphorylation and BTK protein levels, as well as attenuation of downstream signaling. Ex vivo treatment of patient-derived CLL samples and in vivo murine models corroborated these results. The authors conclude that UVI5008 could be a promising alternative to current BTK inhibitors.