UVI5008: the first reversible, non-covalent Bruton's tyrosine kinase epi-inhibitor for B-cell malignancies

Chronic lymphocytic leukemia (CLL) can still 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, especially targeting resistance.

Kinase activity screening was performed on UVI5008, followed by computational study. The findings were validated through a comprehensive set of in vitro and ex vivo assays, including enzymatic, cellular, transcriptional, genetic, epigenetic, and genomic assays, on primary CLL patient-derived peripheral blood mononuclear cells and cell lines, as well as through in vivo studies using genetically engineered mouse models.

We identified a novel tyrosine kinase inhibitory activity of UVI5008, currently the only known epigenetic modulator (epi-inhibitor) that directly targets Bruton's tyrosine kinase (BTK), affecting both BTK expression and enzymatic function. Our comprehensive analysis, combining in silico, ex vivo, and in vivo approaches, revealed that UVI5008 effectively inhibits both wild-type BTK and the C481S mutated BTK isoform, commonly associated with BTK-inhibitor resistance in CLL. Treatment with UVI5008 in B-cell lymphoma and leukemia disorders led to a substantial increase in cellular apoptosis, accompanied by a notable reduction in phosphorylation and BTK protein levels, as well as attenuation of downstream signaling, thus demonstrating superior efficacy compared to ibrutinib. Ex vivo treatment of patient-derived CLL samples and in vivo murine models corroborated these results, further supporting the potential of UVI5008 as a promising therapeutic agent.

UVI5008 represents a promising pharmacological alternative to current BTK inhibitors. As the first-in-class, non-covalent, reversible, BTK inhibitor and epi-inhibitor of expression. UV15008 demonstrates potent in vitro anti-tumor efficacy in relapsed/refractory CLL cells, including cases with the C481S BTK mutation and in in vivo animal studies.