1H-Indazoles derivatives targeting PI3K/AKT/mTOR pathway: Synthesis, anti-tumor effect and molecular mechanism

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Cancer Research

Background:

• The PI3K/AKT/mTOR pathway is frequently activated in tumors, driving cancer cell growth, proliferation, migration, invasion, and angiogenesis.
• Targeting this pathway is a key strategy in cancer therapy.
• Developing novel inhibitors with broad-spectrum activity and favorable pharmacokinetic profiles is crucial.

Purpose of the Study:

• To synthesize and evaluate novel 3-amino-1H-indazole derivatives as potential anticancer agents.
• To investigate the antiproliferative activity and mechanism of action of these compounds.
• To assess their potential as PI3K/AKT/mTOR inhibitors and anti-gastric cancer reagents.

Main Methods:

• Synthesis of a series of 3-amino-1H-indazole derivatives.
• In vitro antiproliferative activity evaluation against multiple cancer cell lines (HT-29, MCF-7, A-549, HepG2, HGC-27).
• Mechanism studies including cell cycle analysis, apoptosis assays, ROS and mitochondrial membrane potential measurements, and analysis of EMT-related proteins and gene expression.

Main Results:

• Compound W24 demonstrated broad-spectrum antiproliferative activity (IC50 values 0.43-3.88 μM) against four cancer cell lines.
• W24 induced G2/M cell cycle arrest and apoptosis by regulating key proteins (Cyclin B1, BAD, Bcl-xL).
• W24 inhibited migration and invasion by downregulating EMT markers (Snail, Slug, HIF-1α) and affected ROS and mitochondrial potential.
• W24 showed low toxicity and good in vivo pharmacokinetics.

Conclusions:

• 3-amino-1H-indazole derivatives represent a promising scaffold for developing novel PI3K/AKT/mTOR inhibitors.
• Compound W24 exhibits significant potential as an anticancer agent, particularly against gastric cancer.
• Further development of these compounds could lead to new therapeutic strategies for various cancers.