Discovery of Pyrimidine- and Coumarin-Linked Hybrid Molecules as Inducers of JNK Phosphorylation through ROS...

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• HER2-positive breast cancer (BC) is associated with aggressive disease, early relapse, and poor outcomes.
• There is a critical need for targeted therapies to improve treatment efficacy and patient prognosis in HER2-positive BC.

Purpose of the Study:

• To design and synthesize a novel JNK-targeting compound for HER2-positive BC.
• To evaluate the efficacy and mechanism of action of the lead compound PC-12 in HER2-positive BC cells.

Main Methods:

• Synthesis and characterization of a pyrimidine- and coumarin-linked JNK inhibitor (PC-12).
• In vitro assessment of PC-12's effects on HER2-positive and HER2-negative BC cell proliferation, DNA damage, and apoptosis.
• Analysis of molecular targets including PARP cleavage, IAP-1, BCL-2, SURVIVIN, and CYCLIN D1 expression.
• In silico docking studies and in vitro JNK phosphorylation assays.

Main Results:

• PC-12 selectively inhibited the proliferation of HER2-positive BC cells.
• PC-12 induced significant DNA damage and apoptosis in HER2-positive BC cells compared to HER2-negative cells.
• PC-12 treatment led to PARP cleavage and downregulation of key proteins (IAP-1, BCL-2, SURVIVIN, CYCLIN D1).
• Computational and experimental data confirmed PC-12's interaction with JNK and enhancement of JNK phosphorylation via ROS generation.

Conclusions:

• The novel compound PC-12 demonstrates potent anti-cancer activity against HER2-positive BC cells.
• PC-12 functions by inducing DNA damage, apoptosis, and modulating key cellular pathways through JNK inhibition.
• These findings support the development of JNK-targeting agents like PC-12 for HER2-positive breast cancer therapy.