In vitro activity: UNC-926 is an inhibitor of the L3MBTL1 (Lethal(3)malignant brain tumor-like protein) domain. It binds to the MBT domain of the L3MBTL1 protein with a Kd value of 3.9 μM. The interaction between methyl-lysine binding proteins and methylated histones plays a crucial role in the regulation of gene expression. UNC-926 was demonstrated to successfully inhibit the recognition of H4K20me1 by L3MBTL1 in the context of an affinity pull down assay. Mounting evidence suggests that epigenetic alterations relate to various human diseases including inflammation, brain disorders, metabolic diseases, and cancer.1, 2, 3 One such epigenetic modification is histone lysine methylation.

Kinase Assay: UNC-926 inhibits L3MBTL1 with an IC50 of 3.9 μM. L3MBTL1UNC-926 also exhibits a low micromolar affinity for the close homolog, L3MBTL3, with a decrease in affinity for the other MBT domains and no binding to CBX7. UNC-926 inhibits binding of the 3xMBT domain to H4K20me1. It selectively inhibits the L3MBTL13xMBT-H4K20me1 interaction in a dose-dependent manner. UNC-926 does not have an effect on the binding of 53BP1 to H4K20me1, demonstrating specificity of UNC-926 for L3MBTL1 over 53BP1