(18)F-Labeled PET Probe Targeting Enhancer of Zeste Homologue 2 (EZH2) for Cancer Imaging
| Autor: | Lihai Yu, Nikola Despotovic, Leonard G. Luyt, Christopher L. Pin, Michael S. Kovacs |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
chemistry.chemical_classification
Organic Chemistry EZH2 Cancer Cancer imaging macromolecular substances medicine.disease Pediatrics Biochemistry Enhancer of zeste homologue 2 (EZH2) fluorine-18 positron emission tomography (PET) pancreatic cancer epigenetics Enzyme chemistry Pancreatic cancer Drug Discovery Histone methylation Cancer research medicine Epigenetics Enhancer |
| Zdroj: | Paediatrics Publications |
| Popis: | [Image: see text] The enzyme enhancer of zeste homologue 2 (EZH2) plays a catalytic role in histone methylation (H3K27me3), one of the epigenetic modifications that is dysregulated in cancer. The development of a positron emission tomography (PET) imaging agent targeting EZH2 has the potential to provide a method of stratifying patients for epigenetic therapies. In this study, we designed and synthesized a series of fluoroethyl analogs based upon the structure of EZH2 inhibitors UNC1999 and EPZ6438. Among the candidate compounds, 20b exhibited a high binding affinity to EZH2 (IC(50) = 6 nM) with selectivity versus EZH1 (IC(50) = 200 nM) by SAM competition assay, and furthermore, EZH2 inhibition was demonstrated in the pancreatic cancer cell line PANC-1 (IC(50) = 9.8 nM). [(18)F]20b was synthesized successfully and showed 5-fold higher uptake in PANC-1 cells than in MCF-7 cells. MicroPET imaging in a PANC-1 cell xenograft mouse model indicates that [(18)F]20b has specific binding to EZH2, which was identified by ex vivo Western blot analysis of the tumor tissue. |
| Databáze: | OpenAIRE |
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