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Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
Synthesis and biological evaluation of niclosamide PROTACs
Erick Munoz1, Guanglin Chen1, Ahamed Hossain2
1Department of Chemistry, California State University, Fresno, 2555 E. San Ramon Avenue, M/S SB70, Fresno, CA 93740, USA.
Abstract:
Roughly 268,000 new cases of prostate cancer and 34,000 deaths from prostate cancer are projected by the American Cancer Society to occur in the United States in 2022. Androgen receptor is a key protein in the proliferation and survival of prostate cancer cells and has been revealed to be overexpressed in 30% to 50% of castration-resistant prostate cancer patients. One promising approach to reducing the level of this protein is Proteolysis Targeting Chimeras (PROTACs) that is an emerging drug discovery technology. PROTACs are hetero-bifunctional molecules where one end binds to a protein of interest and the other to an E3 ligase ligand, initiating the Ubiquitin-Proteasome Pathway for protein degradation. Two PROTACs with niclosamide as androgen receptor ligand and VHL-032 as the E3 ligase ligand have been designed and synthesized for suppressing proliferation of androgen receptor-positive prostate cancer cells via degrading androgen receptor. The in vitro antiproliferative assessment suggested that they can selectively suppress PC-3, LNCaP, and 22Rv1 prostate cancer cell proliferation, but cannot inhibit DU145 cell proliferation. However, the mechanism of both compounds in suppressing prostate cancer cell proliferation is not through the AR PROTAC mechanism because they did not degrade AR in our Western Blotting assay up to 1 µM.
Insights
New Proteolysis Targeting Chimeras (PROTACs) show antiproliferative effects on prostate cancer cells. However, they do not degrade the androgen receptor (AR) as hypothesized, suggesting a different mechanism of action for these novel compounds.
Area of Science:
- Oncology
- Drug Discovery
- Molecular Biology
Background:
- Prostate cancer is a significant health concern in the US, with androgen receptor (AR) overexpression common in castration-resistant cases.
- Proteolysis Targeting Chimeras (PROTACs) offer a novel therapeutic strategy by inducing targeted protein degradation.
- AR is a critical target for prostate cancer treatment, making its degradation a promising approach.
Purpose of the Study:
- To design and synthesize novel PROTACs utilizing niclosamide as an AR ligand and VHL-032 as an E3 ligase ligand.
- To evaluate the in vitro antiproliferative efficacy of these PROTACs against androgen receptor-positive prostate cancer cell lines.
- To investigate the mechanism of action, specifically whether AR degradation occurs.
Main Methods:
- Synthesis of two PROTAC molecules.
- In vitro antiproliferative assays using PC-3, LNCaP, 22Rv1, and DU145 prostate cancer cell lines.
- Western Blotting assay to assess Androgen Receptor (AR) protein levels.
Main Results:
- The synthesized PROTACs selectively suppressed the proliferation of PC-3, LNCaP, and 22Rv1 cell lines.
- DU145 cell proliferation was not inhibited by the PROTACs.
- Western Blotting assays indicated no significant degradation of AR protein up to 1 µM concentration, questioning the PROTAC mechanism.
Conclusions:
- The developed PROTACs exhibit antiproliferative activity against specific prostate cancer cell lines.
- The observed anti-proliferative effects do not appear to be mediated by the intended AR degradation via the PROTAC mechanism.
- Further research is needed to elucidate the precise mechanism underlying the antiproliferative activity of these compounds.
