Z16

Z16 is a selective proteolysis-targeting chimera (PROTAC) designed to induce the degradation of histone deacetylase 8 (HDAC8). It is being investigated for the treatment of acute myeloid leukemia (AML), where it has demonstrated the ability to induce myeloid differentiation across various genetic subtypes, including KMT2A-rearranged (KMT2Ar), NPM1-mutant, and NUP98-upregulated AML. Z16 functions by selectively degrading HDAC8 at low nanomolar concentrations, which impacts the acetylation status of both histone and non-histone proteins, such as PHF14/5 and O-linked N-acetylglucosamine transferase (OGT). In preclinical studies, Z16 has shown significant synergy with Menin-KMT2A inhibitors like revumenib, enhancing differentiation and potentially overcoming resistance in Menin-non-responsive models by modulating the KMT2A machinery and oncogenic gene transcription.