Evaluation of the Safety, Efficacy, and Pharmacokinetics of NBM-BMX in Patients With Metastatic Uveal Melanoma

NBM-BMX is a small molecule inhibitor of HDAC8. The majority of metastasizing uveal melanoma (UM) cases are characterized by the presence of BAP1 mutations. However, as BAP1 mutations lead to a loss of function, therapeutic strategies have primarily focused on exploiting vulnerabilities resulting from BAP1 loss or targeting downstream effectors affected by the BAP1-deficient phenotype. In uveal melanocytes, the absence of BAP1 disrupts their differentiated cell identity, potentially contributing to the metastatic behavior observed in BAP1-mutant UM cells. This differentiation block in the melanocytic lineage is thought to be influenced, at least in part, by the activation of HDAC8 downstream, which leads to the repression of differentiation genes through acetylation of the histone H3K27 at the promoter and enhancers associated with these genes. Consequently, inhibiting HDAC8 could potentially reverse the differentiation block caused by the loss of BAP1.