L61H46 shows potent efficacy against human pancreatic cancer through inhibiting STAT3 pathway

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Pancreatic cancer is a leading cause of cancer mortality globally, necessitating novel therapeutic strategies.
• Constitutive activation of Signal Transducer and Activator of Transcription 3 (STAT3) is implicated in pancreatic cancer progression.
• There is a critical unmet need for clinically viable small-molecule inhibitors targeting STAT3 in pancreatic cancer.

Purpose of the Study:

• To identify and characterize a novel small molecule inhibitor targeting STAT3 signaling in pancreatic cancer.
• To evaluate the efficacy and safety of the identified compound in preclinical models.

Main Methods:

• Bioassay screening and molecular docking were employed to identify L61H46.
• In vitro assays assessed L61H46's effects on pancreatic cancer cell viability and colony formation.
• In vivo studies utilized a BXPC-3 xenograft model to evaluate tumor growth suppression and safety.

Main Results:

• L61H46 demonstrated potent inhibition of pancreatic cancer cell viability and colony formation (IC50: 0.86–2.83 µM).
• The compound effectively inhibited STAT3 phosphorylation and nuclear translocation, without affecting STAT1 phosphorylation.
• L61H46 significantly suppressed tumor growth in vivo and exhibited no observable toxicity in liver, heart, or kidney cells.

Conclusions:

• L61H46 is a potent inhibitor of STAT3 signaling with significant preclinical efficacy in pancreatic cancer models.
• These findings support the further development of L61H46 as a potential therapeutic agent for pancreatic cancer.