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Updated: Aug 1, 2025
Simultaneous Measurement of HDAC1 and HDAC6 Activity in HeLa Cells Using UHPLC-MS
Published on: August 10, 2017
Discovery of highly potent HDAC8 PROTACs with anti-tumor activity
Chunlong Zhao1, Deng Chen1, Fengzhi Suo1
1Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Antonius Deusinglaan 1, 9713AV Groningen, The Netherlands.
Abstract:
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 inducers 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 nanomolar DC50 values and over 95% Dmax in both triple-negative breast cancer MDA-MB-231 cells and T-cell leukemia 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.
Insights
Researchers developed CT-4, a potent HDAC8 degrader using PROTAC technology. This novel approach shows promise for treating diseases linked to aberrant histone deacetylase 8 (HDAC8) function.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Aberrant histone deacetylase 8 (HDAC8) function is linked to various diseases.
- Targeting HDAC8's structural or catalytic functions is crucial for therapeutic development.
- HDAC8 degradation inducers may offer advantages over traditional HDAC8 inhibitors.
Purpose of the Study:
- To develop a selective and potent HDAC8 degradation inducer using proteolysis targeting chimera (PROTAC) technology.
- To evaluate the efficacy of the developed compound, CT-4, in cancer and leukemia cell lines.
Main Methods:
- Utilized PROTAC strategy to design and synthesize CT-4, an HDAC8 degradation inducer.
- Assessed CT-4's potency using DC50 and Dmax values in MDA-MB-231 and Jurkat cells.
- Evaluated anti-migration and anti-proliferative effects in triple-negative breast cancer cells.
- Measured apoptotic cell death induction in T-cell leukemia cells via caspase 3/7 assay and flow cytometry.
Main Results:
- CT-4 demonstrated single-digit nanomolar DC50 values and over 95% Dmax in both cell lines.
- CT-4 exhibited potent anti-migration but limited anti-proliferative activity in MDA-MB-231 cells.
- CT-4 effectively induced apoptotic cell death in Jurkat cells.
Conclusions:
- HDAC8 degradation inducers, like CT-4, are promising therapeutic agents.
- Targeted degradation of HDAC8 holds potential for treating HDAC8-related diseases.
- Differential cellular responses highlight the tissue-specific therapeutic potential of HDAC8 modulation.
