Exploration of Hydrazide-Based HDAC8 PROTACs for the Treatment of Hematological Malignancies and Solid Tumors

HDAC8 can mediate signals by using its enzymatic or nonenzymatic functions, which are expected to be critical for various types of cancer. Herein, we employed proteolysis targeting chimera (PROTAC) technology to target the enzymatic as well as the nonenzymatic functions of HDAC8. A potent and selective HDAC8 PROTAC Z16 (CZH-726) with low nanomolar DC₅₀ values in various cell lines was identified. Interestingly, Z16 induced structural maintenance of chromosomes protein 3 (SMC3) hyperacetylation at low concentrations and histone hyperacetylation at high concentrations, which can be explained by HDAC8 degradation and off-target HDAC inhibition, respectively. Notably, Z16 potently inhibited proliferation of various cancer cell lines and the antiproliferative mechanisms proved to be cell-type-dependent, which, to a large extent, is due to off-target HDAC inhibition. In conclusion, we report a hydrazide-based HDAC8 PROTAC Z16, which can be used as a probe to investigate the biological functions of HDAC8.