1,2,4-Amino-triazine derivatives as pyruvate dehydrogenase kinase inhibitors: Synthesis and pharmacological...

Area of Science:

• Biochemistry
• Oncology
• Medicinal Chemistry

Background:

• Cancer cells exhibit metabolic deregulation, a key hallmark promoting resistance and progression.
• Pyruvate dehydrogenase kinases (PDKs) are crucial metabolic regulators overexpressed in aggressive cancers like pancreatic ductal adenocarcinoma (PDAC).
• Limited PDK inhibitors with diverse structures exist, necessitating novel therapeutic approaches.

Purpose of the Study:

• To synthesize and evaluate novel hybrid molecules as potential inhibitors of PDK enzymes.
• To investigate the antiproliferative and mechanistic effects of these compounds on pancreatic cancer cells.
• To assess the in vivo efficacy of these novel inhibitors in a preclinical tumor model.

Main Methods:

• Molecular hybridization combining 1,2,4-amino triazines, 7-azaindoles, and indoles.
• Enzymatic assays to evaluate PDK1 and PDK4 inhibition.
• In vitro antiproliferative assays using 2D and 3D pancreatic cancer cell models.
• Mechanistic studies including apoptosis induction.
• In vivo efficacy studies in a murine syngeneic solid tumor model.

Main Results:

• Novel hybrid molecules effectively inhibited PDK1 and PDK4 enzymatic activity, confirmed by docking studies.
• Synthesized derivatives exhibited significant antiproliferative effects against pancreatic cancer cells in vitro.
• Compounds demonstrated PDK axis inhibition and induced apoptosis in PDAC cells.
• In vivo studies showed tumor growth reduction without significant body weight loss in treated mice.

Conclusions:

• The novel hybrid molecules represent a promising new class of PDK inhibitors.
• These compounds effectively target the PDK pathway, leading to pancreatic cancer cell death and reduced tumor growth.
• The developed inhibitors show translational potential for treating aggressive pancreatic cancer.