Nanoparticles of a Pyrazolo-Pyridazine Derivative as Potential EGFR and CDK-2 Inhibitors: Design, Structure Determination, Anticancer Evaluation and In Silico Studies

Heba E Hashem; Abd El-Galil E Amr; Abdulrahman A Almehizia; Ahmed M Naglah; Benson M Kariuki; Heba A Eassa; Eman S Nossier

doi:10.3390/molecules28217252

Nanoparticles of a Pyrazolo-Pyridazine Derivative as Potential EGFR and CDK-2 Inhibitors: Design, Structure Determination, Anticancer Evaluation and In Silico Studies

Molecules. 2023 Oct 25;28(21):7252. doi: 10.3390/molecules28217252.

Authors

Heba E Hashem¹, Abd El-Galil E Amr², Abdulrahman A Almehizia³, Ahmed M Naglah³, Benson M Kariuki⁴, Heba A Eassa^{5

6}, Eman S Nossier^{7

8}

Affiliations

¹ Department of Chemistry, Faculty of Women, Ain Shams University, Cairo 11757, Egypt.
² Applied Organic Chemistry Department, National Research Center, Cairo 12622, Egypt.
³ Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
⁴ School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, UK.
⁵ Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 11754, Egypt.
⁶ Department of Pharmaceutical Sciences, School of Pharmacy and Physician Assistant Studies, University of Saint Joseph, West Hartford, CT 06117, USA.
⁷ Department of Pharmaceutical Medicinal Chemistry and Drug Design, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 11754, Egypt.
⁸ The National Committee of Drugs, Academy of Scientific Research and Technology, Cairo 11516, Egypt.

Abstract

The strategic planning of this study is based upon using the nanoformulation method to prepare nanoparticles 4-SLNs and 4-LPHNPs of the previously prepared 4,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-3-amine (4) after confirming its structure with single crystal X-ray analysis. These nanoparticles exhibited promising cytotoxic activity against HepG-2, HCT-116 and MCF-7 cancer cell lines in comparison with the reference doxorubicin and the original derivative 4. Moreover, their inhibitory assessment against EGFR and CDK-2/cyclin A2 displayed improved and more favorable impact than the parent 4 and the references. Detection of their influence upon cancer biomarkers revealed upregulation of Bax, p53 and caspase-3 levels and downregulation of Bcl-2 levels. The docking simulation demonstrated that the presence of the pyrazolo[3,4-c]pyridazin-3-amine scaffold is amenable to enclosure and binding well within EGFR and CDK-2 receptors through different hydrophilic interactions. The pharmacokinetic and physicochemical properties of target 4 were also assessed with ADME investigation, and the outcome indicated good drug-like characteristics.

Keywords: ADME analysis; EGFR and CDK-2/cyclin A2 inhibition; cytotoxicity; docking simulation; nanoparticles; pyrazolo[3,4-c]pyridazine.

MeSH terms

Amines / pharmacology
Antineoplastic Agents* / chemistry
Cell Line, Tumor
Cell Proliferation
Drug Screening Assays, Antitumor
ErbB Receptors / metabolism
Humans
Molecular Docking Simulation
Molecular Structure
Nanoparticles*
Protein Kinase Inhibitors / chemistry
Pyridazines* / pharmacology
Structure-Activity Relationship

Substances

Antineoplastic Agents
ErbB Receptors
Pyridazines
Amines
Protein Kinase Inhibitors
EGFR protein, human

Grants and funding

RSPD2023R852/King Saud University, Riyadh, Saudi Arabia through Researchers Supporting