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Updated: Jul 1, 2026
Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
Design and Synthesis of Polyamine-Proteolysis Targeting Chimera Conjugates for Histone Deacetylase (HDAC) Degradation
Yanran Liu1, Wentian Chen1, Yanwei Shang1
1Hangzhou Medical College, Hangzhou, 311399, P. R. China.
Abstract:
Although histone deacetylase (HDAC) inhibitors have demonstrated significant advantages in the field of targeted cancer therapy, numerous adverse events have been observed due to the high doses required to achieve therapeutic effects. Additionally, acquired drug resistance to HDAC inhibitors has also been observed in clinical usage. Given these findings, the development of HDAC degraders may represent a more promising strategy to overcome these limitations due to their specific mechanism of action. In this study, 14 HDAC degraders featuring a polyamine linker are designed and synthesized by conjugating HDAC inhibitors (HDACi, Vorinostat) with Cereblon (CRBN, an E3 ubiquitin ligase ligand). Significantly, compound I exhibited a degradation efficiency of ≈62% at 5 μM in MDA-MB-231 cells. Additionally, compound N exhibited the highest cellular uptake efficiency in a dose- and time-dependent manner. The findings presented in our manuscript provided valuable insights for the development of a proteolysis targeting chimera with high cellular uptake efficiency.
Insights
New HDAC degraders offer a promising cancer therapy strategy. These compounds, designed with polyamine linkers, show high degradation efficiency and cellular uptake, potentially overcoming limitations of current HDAC inhibitors.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- Histone deacetylase (HDAC) inhibitors are used in cancer therapy but require high doses, leading to adverse events and drug resistance.
- Developing HDAC degraders presents a more targeted approach to overcome these limitations.
Purpose of the Study:
- To design and synthesize novel HDAC degraders by conjugating HDAC inhibitors with Cereblon (CRBN) ligand using a polyamine linker.
- To evaluate the degradation efficiency and cellular uptake of the synthesized compounds.
Main Methods:
- Conjugation of Vorinostat (HDAC inhibitor) with CRBN ligand via a polyamine linker to create 14 novel HDAC degraders.
- Assessment of compound degradation efficiency in MDA-MB-231 cells.
- Evaluation of cellular uptake efficiency in a dose- and time-dependent manner.
Main Results:
- Compound I demonstrated significant HDAC degradation efficiency (≈62% at 5 μM in MDA-MB-231 cells).
- Compound N exhibited superior cellular uptake efficiency, which was dependent on both dose and time.
- The study successfully developed novel proteolysis targeting chimeras with improved characteristics.
Conclusions:
- The synthesized HDAC degraders show potential as a more effective cancer therapy strategy.
- The findings provide valuable insights for developing proteolysis targeting chimeras with enhanced cellular uptake.
- This approach may overcome the limitations associated with traditional HDAC inhibitors.
