Discovery of 12O-A Novel Oral Multi-Kinase Inhibitor for the Treatment of Solid Tumor

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Pharmacology

Background:

• Developing novel anticancer agents is crucial for treating human solid tumors.
• Pyrimidine-benzotriazole derivatives represent a potential class of anticancer compounds.

Purpose of the Study:

• To synthesize and evaluate novel pyrimidine-benzotriazole derivatives for anticancer activity.
• To identify and characterize the most potent compound, focusing on its mechanism of action and in vivo efficacy.

Main Methods:

• Synthesis of pyrimidine-benzotriazole derivatives.
• In vitro antiproliferative assays against human solid tumor cell lines.
• Kinase inhibition assays and molecular docking studies.
• In vivo efficacy study using an SiHa xenograft mouse model.

Main Results:

• Compound 12O exhibited significant antiproliferative activity against SiHa cells (IC50 = 0.009 μM).
• 12O demonstrated multi-kinase inhibitory activity against cyclin-dependent kinases (CDKs) and fms-like tyrosine kinase (FLT) in the nanomolar range.
• Molecular docking confirmed the importance of the triazole moiety for CDK inhibition.
• 12O inhibited cancer cell proliferation, colony formation, cell cycle progression, and induced apoptosis in vitro.
• In vivo, 12O (20 mg/kg daily) suppressed SiHa tumor growth in mice without apparent toxicity.

Conclusions:

• Compound 12O is a highly promising anticancer agent with potent activity against SiHa cells.
• 12O functions as a multi-kinase inhibitor targeting CDKs and FLT.
• The findings support 12O as a valuable lead for developing novel CDK and FLT inhibitors for cancer therapy.