Related Experiment Video
Updated: Jun 14, 2025
Simultaneous Measurement of HDAC1 and HDAC6 Activity in HeLa Cells Using UHPLC-MS
Published on: August 10, 2017
Searching for Novel HDAC6/Hsp90 Dual Inhibitors with Anti-Prostate Cancer Activity: In Silico Screening and In Vitro
Luca Pinzi1, Silvia Belluti1, Isabella Piccinini1
1Department of Life Sciences, University of Modena and Reggio Emilia, Via Giuseppe Campi 103, 41125 Modena, Italy.
Abstract:
Prostate cancer (PCA) is one of the most prevalent types of male cancers. While current treatments for early-stage PCA are available, their efficacy is limited in advanced PCA, mainly due to drug resistance or low efficacy. In this context, novel valuable therapeutic opportunities may arise from the combined inhibition of histone deacetylase 6 (HDAC6) and heat shock protein 90 (Hsp90). These targets are mutually involved in the regulation of several processes in cancer cells, and their inhibition is demonstrated to provide synergistic effects against PCA. On these premises, we performed an extensive in silico virtual screening campaign on commercial compounds in search of dual inhibitors of HDAC6 and Hsp90. In vitro tests against recombinant enzymes and PCA cells with different levels of aggressiveness allowed the identification of a subset of compounds with inhibitory activity against HDAC6 and antiproliferative effects towards LNCaP and PC-3 cells. None of the candidates showed appreciable Hsp90 inhibition. However, the discovered compounds have low molecular weight and a chemical structure similar to that of potent Hsp90 blockers. This provides an opportunity for structural and medicinal chemistry optimization in order to obtain HDAC6/Hsp90 dual modulators with antiproliferative effects against prostate cancer. These findings were discussed in detail in the study.
Insights
Researchers screened compounds for dual inhibition of HDAC6 and Hsp90 to treat advanced prostate cancer (PCA). While compounds inhibited HDAC6 and reduced PCA cell growth, Hsp90 inhibition was not observed, suggesting optimization potential.
Area of Science:
- Oncology
- Medicinal Chemistry
- Biochemistry
Background:
- Prostate cancer (PCA) presents limited treatment options for advanced stages due to drug resistance.
- Combined inhibition of histone deacetylase 6 (HDAC6) and heat shock protein 90 (Hsp90) offers potential synergistic effects against PCA.
- HDAC6 and Hsp90 play crucial roles in regulating cancer cell processes.
Purpose of the Study:
- To identify novel dual inhibitors targeting both HDAC6 and Hsp90 for advanced prostate cancer treatment.
- To perform in silico virtual screening of commercial compounds for potential dual inhibitors.
- To evaluate the in vitro efficacy of identified compounds against PCA cells.
Main Methods:
- Extensive in silico virtual screening of commercial compound libraries.
- In vitro enzyme inhibition assays against recombinant HDAC6.
- Antiproliferative assays using LNCaP and PC-3 prostate cancer cell lines.
Main Results:
- A subset of compounds demonstrated significant HDAC6 inhibitory activity.
- Identified compounds exhibited antiproliferative effects on LNCaP and PC-3 cells.
- No compounds showed significant Hsp90 inhibition, but possessed structural similarities to known Hsp90 inhibitors.
Conclusions:
- The identified compounds are promising starting points for developing novel HDAC6/Hsp90 dual modulators.
- Further medicinal chemistry optimization is warranted to enhance Hsp90 inhibitory activity.
- These optimized compounds could offer improved therapeutic strategies for advanced prostate cancer.
Related Concept Videos
02:34Inhibition of Cdk Activity
01:28Treatment for Pulmonary Arterial Hypertension: Phosphodiesterase Inhibitors
Among the PDE5 inhibitors, sildenafil (Revatio) stands out as a competitive and selective inhibitor. It operates by elevating cellular levels of cGMP and augmenting signaling through the cGMP-PKG pathway, promoting vasodilation. Upon oral...
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
01:23Treatment for Pulmonary Arterial Hypertension: Prostacyclin Receptor Agonists
These agonists bind to the IPR receptor situated on the plasma membrane of the pulmonary artery smooth muscle cells. This binding triggers a cascade of reactions known as the GS-AC-cAMP-PKA pathway. This pathway results in the relaxation of smooth muscle...