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Exploring Pyrazolo[3,4-b]Pyridine and Spiro-Oxindole Hybrids as Selective CDK2 or EGFR Inhibitors for Targeted Cancer
Ahmed K B A W Farouk1,2, Aya A A Al-Tanany3,4, Mohamed R Elnagar5,6
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Drug Development Research
|March 9, 2026
Summary
New anticancer drug candidates, pyrazolo[3,4-b]pyridine and spiro-oxindole derivatives, show potent inhibition of cyclin-dependent kinase 2 (CDK2) and epidermal growth factor receptor (EGFR). Compounds 6e and 8c demonstrate selective cancer cell cytotoxicity and induce apoptosis, highlighting their potential as targeted cancer therapies.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Pharmacology
Background:
- Cancer remains a leading cause of mortality worldwide, necessitating the development of novel targeted therapies.
- Cyclin-dependent kinase 2 (CDK2) and epidermal growth factor receptor (EGFR) are validated targets in various cancers.
- Existing therapies often face challenges with resistance and off-target effects.
Purpose of the Study:
- To design, synthesize, and evaluate novel pyrazolo[3,4-b]pyridine and spiro-oxindole derivatives as potential anticancer agents.
- To assess the inhibitory activity of these compounds against CDK2 and EGFR, including mutant forms.
- To investigate the mechanism of action and selectivity of promising compounds.
Main Methods:
- Rational drug design and chemical synthesis of pyrazolo[3,4-b]pyridine and spiro-oxindole derivatives.
- In vitro kinase inhibition assays (IC50 determination) against CDK2 and EGFR.
- Cytotoxicity assays against cancer cell lines (MCF-7, MDA-MB231) and normal cells (Vero).
- Flow cytometry for cell cycle arrest and apoptosis analysis.
- Molecular docking and molecular dynamics simulations.
Main Results:
- Compounds 6e, 7b, and 7c showed potent CDK2 inhibition (IC50: 0.88, 1.89, 1.23 μM).
- Compounds 8b and 8c exhibited significant EGFR inhibition (IC50: 0.13, 0.09 μM) and activity against mutant EGFRT790M (IC50: 0.32, 0.14 μM).
- Compounds 6e and 8c displayed selective cytotoxicity against cancer cells and induced G1-phase arrest and apoptosis, evidenced by increased Bax/Bcl-2 ratios.
- Computational studies confirmed stable interactions within target protein active sites.
Conclusions:
- Compounds 6e and 8c represent promising lead scaffolds for developing novel CDK2 and EGFR inhibitors.
- These derivatives exhibit potent and selective anticancer activity through cell cycle arrest and apoptosis induction.
- Further preclinical development of these compounds is warranted for targeted cancer therapy.
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