UVI-5008: A A First-in-Class Reversible, Non-Covalent Dual Epigenetic and Kinase Inhibitor Targeting Bruton's Tyrosine Kinase in Resistant B-Cell Malignancies

Epigenomics of B-cell malignancies may explain the intraclonal diversification and help elucidating the reason of emerging relapse and treatment refractoriness/resistance. We identified the first next-generation, selective, reversible, non-covalent BTK-epigenetic inhibitor (BTK-epi-inhibitor) capable of downregulating BTK at both the transcriptional and enzymatic levels.To characterize this molecule, we employed a comprehensive and integrative experimental approach, encompassing genomic, epigenomic, transcriptional, and on-target analyses.

We investigated the molecular and functional mechanisms underlying the activity of UVI5008, while also evaluating its therapeutic efficacy, toxicity, pharmacokinetics, and safety profile. These studies were conducted through a combination of in vitro (cell culture), ex vivo, and in vivo (animal model) experiments, aiming to minimize side effects and off-target toxicity. Importantly, we demonstrated that UVI5008 inhibits both wild-type BTK and the C481S mutant isoform—a key mutation associated with resistance to first-generation BTK inhibitors—across in silico, ex vivo, and in vivo models of chronic lymphocytic leukemia (CLL) and B-cell lymphoma.

Treatment with UVI5008 led to a significant increase in cell death, accompanied by a reduction in BTK protein levels, its phosphorylation, and downstream signaling activity. Taken together, these data highlight the novelty, potency, and clinical relevance of UVI5008 as a new therapeutic strategy for BTK-driven malignancies, especially in relapsed/refractory (R/R) CLL and B-cell lymphoma, where current therapies often fail.