Discovery of highly potent HDAC8 PROTACs with anti-tumor activity

Various diseases are deeply associated with aberrations in HDAC8 functions. These aberrations can be assigned to either structural functions or catalytic functions of HDAC8. Therefore, development of HDAC8 degradation in-ducers might be more promising than HDAC8 inhibitors. We employed the proteolysis targeting chimera (PROTAC) strategy to develop a selective and potent HDAC8 degradation inducer CT-4 with single-digit nano-molar DC50 values and over 95% Dmax in both triple-negative breast cancer MDA-MB-231 cells and T-cell leu-kemia cells. Notably, CT-4 demonstrated potent anti-migration activity and limited anti-proliferative activity in MDA-MB-231 cells. In contrast, CT-4 effectively induced apototic cell death in Jurkat cells, as assessed by a caspase 3/7 activity assay and flow cytometry. Our findings suggest that the development of HDAC8 degradation inducers holds great potential for the treatment of HDAC8-related diseases.

Automated summary

Aberrations in HDAC8 functions are closely linked to various diseases, and development of HDAC8 degradation inducers may be more promising than HDAC8 inhibitors. Using the PROTAC strategy, we developed a selective and potent HDAC8 degradation inducer CT-4 with single-digit nano-molar DC50 values and over 95% Dmax in both MDA-MB-231 cells and T-cell leukemia cells. CT-4 showed potent anti-migration activity and limited anti-proliferative activity in MDA-MB-231 cells, while effectively inducing apoptotic cell death in Jurkat cells. These findings suggest that the development of HDAC8 degradation inducers holds great potential for the treatment of HDAC8-related diseases.