Discovery and Anticancer Screening of Novel Oxindole-Based Derivative Bearing Pyridyl Group as Potent and Selective...

Area of Science:

• Medicinal Chemistry
• Cancer Biology
• Molecular Pharmacology

Background:

• Protein kinases are crucial regulators of cellular functions, with over 60% implicated in cancer as oncoproteins.
• FLT3, a class III receptor tyrosine kinase, is frequently overexpressed in acute leukemia.
• Previous research identified an oxindole-based compound with FLT3 inhibitory activity.

Purpose of the Study:

• To synthesize and evaluate novel oxindole-based compounds for antiproliferative activity.
• To discover potent inhibitors of FLT3 and other cancer-associated kinases.
• To explore novel therapeutic candidates for leukemia and colon cancer.

Main Methods:

• Synthesis of sixteen new oxindole-based compounds.
• Screening against NCI-60 human cancer cell lines for antiproliferative effects.
• Kinase inhibition assays against a panel of 10 carcinogenesis-associated kinases.
• Molecular docking and dynamics simulations for CDK2 and FLT3 active sites.

Main Results:

• Compound 5l demonstrated potent antiproliferative activity against leukemia (GI50 = 3.39 µM) and colon cancer (GI50 = 5.97 µM) cell lines.
• Compound 5l potently inhibited FLT3 (IC50 = 36.21 nM) and CDK2 (IC50 = 8.17 nM).
• Compound 5l exhibited superior CDK2 inhibition compared to sunitinib.
• Molecular modeling provided insights into the binding interactions of compound 5l with CDK2 and FLT3.

Conclusions:

• Compound 5l represents a novel structural scaffold with dual inhibitory activity against CDK2 and FLT3.
• The findings support the further development of compound 5l as a potential therapeutic agent for leukemia and colon cancer.
• Simultaneous inhibition of CDK2 and FLT3 may offer a new therapeutic strategy for specific cancers.