Design, synthesis, and antitumor activity of PLGA nanoparticles incorporating a discovered benzimidazole derivative as EZH2 inhibitor

Hoda A Elkot; Ibrahim Ragab; Noha M Saleh; Mohamed N Amin; Sara T Al-Rashood; Shahenda M El-Messery; Ghada S Hassan

doi:10.1016/j.cbi.2021.109530

Design, synthesis, and antitumor activity of PLGA nanoparticles incorporating a discovered benzimidazole derivative as EZH2 inhibitor

Chem Biol Interact. 2021 Aug 1:344:109530. doi: 10.1016/j.cbi.2021.109530. Epub 2021 May 23.

Authors

Hoda A Elkot¹, Ibrahim Ragab¹, Noha M Saleh², Mohamed N Amin³, Sara T Al-Rashood⁴, Shahenda M El-Messery⁵, Ghada S Hassan⁶

Affiliations

¹ Faculty of Pharmacy, Mansoura University, P.O. Box 35516, Mansoura, Egypt.
² Department of Pharmaceutics, Faculty of Pharmacy, Mansoura University, P.O. Box 35516, Mansoura, Egypt. Electronic address: nunu_ramy@yahoo.com.
³ Department of Biochemistry, Faculty of Pharmacy, Mansoura University, P.O. Box 35516, Mansoura, Egypt.
⁴ Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia.
⁵ Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, P.O. Box 35516, Mansoura, Egypt.
⁶ Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, P.O. Box 35516, Mansoura, Egypt.

PMID: 34029540
DOI: 10.1016/j.cbi.2021.109530

Abstract

Purpose: Targeting enhancer of zeste homolog 2 (EZH2) can represent a hopeful strategy for oncotherapy. Also, the use of PLGA-based nanoparticles as a novel and rate-controlling carrier system was of our concern.

Methods: Benzimidazole derivatives were synthesized, and their structures were clarified. In vitro antitumor activity was evaluated. Then, a modeling study was performed to investigate the ability of the most active compounds to recognize EZH2 active sites. Compound 30 (Drug) was selected to conduct pre-formulation studies and then it was incorporated into polymeric PLGA nanoparticles (NPs). NPs were then fully characterized to select an optimized formula (NP₄) that subjected to further evaluation regarding antitumor activity and protein expression levels of EZH2 and EpCAM.

Results: The results showed the antitumor activity of some synthesized derivatives. Docking outcomes demonstrated that Compound 30 was able to identify EZH2 active sites. NP₄ exhibited promising findings and proved to keep the antitumor activity of Compound 30. HEPG-2 was the most sensitive for both Drug and NP₄. Protein analysis indicated that Drug and NP₄ had targeted EZH2 and the downstream signaling pathway leading to the decline of EpCAM expression.

Conclusions: Targeting EZH2 by Compound 30 has potential use in the treatment of cancer especially hepatocellular carcinoma.

Keywords: Antitumor activity; EZH2 inhibitor; EpCAM; Nanoparticles; PLGA; Synthesis.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology*
Benzimidazoles / chemical synthesis
Benzimidazoles / metabolism
Benzimidazoles / pharmacology*
Binding Sites
Cell Line, Tumor
Drug Carriers / chemistry*
Drug Liberation
Drug Screening Assays, Antitumor
Enhancer of Zeste Homolog 2 Protein / chemistry
Enhancer of Zeste Homolog 2 Protein / metabolism*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology*
Epithelial Cell Adhesion Molecule / metabolism
Humans
Molecular Docking Simulation
Molecular Structure
Nanoparticles / chemistry*
Polycomb Repressive Complex 2 / chemistry
Polycomb Repressive Complex 2 / metabolism
Polylactic Acid-Polyglycolic Acid Copolymer / chemistry
Protein Binding
Solubility
Structure-Activity Relationship

Substances

Antineoplastic Agents
Benzimidazoles
Drug Carriers
EPCAM protein, human
Enzyme Inhibitors
Epithelial Cell Adhesion Molecule
Polylactic Acid-Polyglycolic Acid Copolymer
EZH2 protein, human
Enhancer of Zeste Homolog 2 Protein
Polycomb Repressive Complex 2