Integrated structure- and ligand-based design, synthesis, and biological evaluation of potent thiazole-based multi-kinase PI3Kα and CDK2/8 inhibitors as anticancer agents

Abdalla R Mohamed; Ahmed M El Kerdawy; Mohamed R Elnagar; Mohamed H Younis; Abdullah Y A Alzahrani; Sana B Moussa; Hanan H Georgey; Nagwa M Abdel Gawad; Eman R Mohammed

doi:10.1016/j.ejmech.2025.117902

Integrated structure- and ligand-based design, synthesis, and biological evaluation of potent thiazole-based multi-kinase PI3Kα and CDK2/8 inhibitors as anticancer agents

Eur J Med Chem. 2025 Jun 24:296:117902. doi: 10.1016/j.ejmech.2025.117902. Online ahead of print.

Authors

Abdalla R Mohamed¹, Ahmed M El Kerdawy², Mohamed R Elnagar³, Mohamed H Younis⁴, Abdullah Y A Alzahrani⁵, Sana B Moussa⁵, Hanan H Georgey⁶, Nagwa M Abdel Gawad⁷, Eman R Mohammed⁷

Affiliations

¹ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo, 11829, Egypt. Electronic address: abdallaharafa@eru.edu.eg.
² School of Health and Care Sciences, College of Health and Science, University of Lincoln, Joseph Banks Laboratories, Green Lane, Lincoln, United Kingdom; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, 11562, Egypt.
³ Pharmacology and Toxicology Department, Faculty of Pharmacy, Al-Azhar University, Cairo, 11823, Egypt; Department of Pharmacology, College of Pharmacy, The Islamic University, Najaf, 54001, Iraq.
⁴ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo, 11829, Egypt.
⁵ Department of Chemistry, Faculty of Science, King Khalid University, Abha, 61413, Saudi Arabia.
⁶ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, 11562, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University, 11786, Cairo, Egypt.
⁷ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, 11562, Egypt.

PMID: 40578250
DOI: 10.1016/j.ejmech.2025.117902

Abstract

A small library of novel potential multi-kinase inhibitors was designed by integrating structure- and ligand-based design approaches through terms of hybridization and fragment-based design tools. The required key pharmacophoric features for the individual kinases' inhibition were fused to achieve the desired inhibitory activity against PI3Kα and CDK2, relying on our previously studied strategy of the structure- and ligand-based design approaches' expansion. Thus, all the synthesized compounds were evaluated for their inhibitory activity against PI3Kα and CDK2/cyclin A2, in addition to CDK8/cyclin C. The newly synthesized compounds exhibited a promising activity at sub-micromolar concentrations toward the three enzymes, indicating the efficacy of the adopted strategies utilized in the current design. Additionally, all the new derivatives were evaluated for their antiproliferative activity at 10 μM against the full NCI-60 cell panel. Compounds 3d, 10b and 11e revealed the highest mean growth inhibition (78.10, 67.41and 73.22 %, respectively). Compounds 3d, 10b and 11e were selected for five-dose assay, where the results indicated higher activity against leukemia (MG-MID = 2.87, 2.65 and 2.74 μM, respectively), and breast cancer (MG-MID = 3.79, 3.29 and 3.34 μM, respectively). Compound 10b displayed a potential activity against Leukemia SR cell line with GI₅₀ of 0.47 μM. In vitro normal Vero cell line cytotoxicity was conducted as well indicating non-significant cytotoxic effect. Modeling studies were achieved for the newly synthesized compounds within the crystal structures of PI3Kα and CDK2, along with CDK8, which augment the biological screening and insightfully validated the utilized design approach.

Keywords: Anticancer; CDK2; Ligand-based design; PI3Kα; Structure-based design.