Discovery of a novel STAT3 inhibitor: A potential application for pancreatic cancer treatment

Area of Science:

• Oncology
• Pharmacology
• Computational Chemistry

Background:

• Pancreatic ductal adenocarcinoma (PDAC) presents a significant global health challenge, with high mortality rates and limited treatment options for advanced disease.
• Current chemotherapy regimens offer modest survival benefits, highlighting an urgent need for innovative therapeutic strategies.
• The natural compound palmatine has shown promise in inhibiting pancreatic cancer growth and enhancing gemcitabine efficacy.

Purpose of the Study:

• To investigate the interaction of palmatine with the STAT3 linker domain using computational docking.
• To identify novel compounds with enhanced STAT3 binding capabilities for potential PDAC therapy.
• To evaluate the efficacy of identified compounds, particularly Striatal B, in inhibiting pancreatic cancer cell growth and potentiating chemotherapy.

Main Methods:

• Computational docking simulations were employed to analyze palmatine's interaction with the STAT3 linker domain.
• A large-scale virtual screening of 139,735 compounds from the National Cancer Institute Developmental Therapeutics Program was conducted to identify STAT3 binders.
• In vitro assays were performed to assess the anti-cancer effects of lead compounds, including Striatal B, on pancreatic cancer cells and their interaction with gemcitabine.

Main Results:

• Computational analysis revealed palmatine's interaction with the STAT3 linker domain.
• Striatal B was identified as a lead compound with superior STAT3 binding affinity compared to palmatine.
• In vitro studies demonstrated that Striatal B significantly inhibited pancreatic cancer cell proliferation and enhanced gemcitabine's therapeutic effect.
• Striatal B reduced STAT3 activation, suppressed epithelial-mesenchymal transition markers, and modulated cellular mechanical properties.

Conclusions:

• Striatal B exhibits potent anti-cancer activity against pancreatic cancer cells, both independently and in combination with gemcitabine.
• The compound's mechanism of action appears to involve the modulation of STAT3 signaling and cellular mechanics.
• Striatal B represents a promising novel therapeutic candidate for the treatment of pancreatic ductal adenocarcinoma (PDAC).