HDAC11 mediates the ubiquitin-dependent degradation of p53 and inhibits the anti-leukemia effect of PD0166285

Cytarabine-resistant acute myeloid leukemia (AML) is a common phenomenon, necessitating the search for new chemotherapeutics. WEE1 participates in cell cycle checkpoint signaling and inhibitors targeting WEE1 (WEE1i) constitute a potential novel strategy for AML treatment. HDAC (histone deacetylase) inhibitors have been shown to enhance the anti-tumor effects of WEE1i but molecular mechanisms of HDAC remain poorly characterized. In this study, the WEE1 inhibitor PD0166285 showed a relatively good anti-leukemia effect. Notably, PD0166285 can arise the expression of HDAC11 which was negatively correlated with survival of AML patients. Moreover, HDAC11 can reduced the anti-tumor effect of PD0166285 through an effect on p53 stability and the changes in phosphorylation levels of MAPK pathways. Overall, the cell cycle inhibitor, PD0166285, is a potential chemotherapeutic drug for AML. These fundings contribute to a functional understanding of HDAC11 in AML.

 

Comments:

The passage you provided discusses the potential of a WEE1 inhibitor, PD0166285, as a treatment for acute myeloid leukemia (AML) and explores the role of HDAC11 in this context. Here's a breakdown of the key points from the passage:

1. **Cytarabine-Resistant AML:** Cytarabine resistance in AML patients is a common problem, prompting the search for new chemotherapeutic options.

2. **WEE1 Inhibitors as Treatment:** WEE1 is a protein involved in cell cycle checkpoint signaling. Inhibitors targeting WEE1 (WEE1i) are being considered as a potential novel strategy for AML treatment.

3. **HDAC Inhibitors:** HDAC inhibitors have been studied for their ability to enhance the anti-tumor effects of WEE1 inhibitors. HDACs are histone deacetylase enzymes that play a role in gene regulation by modifying chromatin structure.

4. **PD0166285 as a WEE1 Inhibitor:** PD0166285, a specific WEE1 inhibitor, demonstrated a strong anti-leukemia effect in the study.

5. **HDAC11 Expression:** PD0166285 was found to increase the expression of HDAC11. High levels of HDAC11 were negatively correlated with the survival of AML patients.

6. **Impact of HDAC11:** HDAC11 was observed to reduce the anti-tumor effect of PD0166285. It affected the stability of p53, a tumor suppressor protein, and influenced the phosphorylation levels of MAPK (Mitogen-Activated Protein Kinase) pathways.

7. **Conclusion:** PD0166285, as a cell cycle inhibitor, has the potential to be a chemotherapeutic drug for AML. Additionally, understanding the functional role of HDAC11 in AML could provide valuable insights for future research and therapeutic development.

In summary, the study suggests that targeting WEE1 using PD0166285 could be a promising approach for treating AML, but the effectiveness of this treatment might be influenced by the levels and activity of HDAC11 in AML cells. Further research is needed to explore these molecular mechanisms and develop more effective therapies for AML patients.

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S8148	PD0166285	PD0166285 is a potent Wee1 and Chk1 inhibitor with activity at nanomolar concentrations (IC50=24 nM for Wee1 and 72 nM for Myt1). PD0166285 is also a novel G2 checkpoint abrogator. PD0166285 induces apoptosis.

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