Design, Synthesis, and Bioactivity Evaluation of a Palmitoyltransferase Inhibitor Based on the PAP Structure

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Oncology

Background:

• Protein palmitoylation is a critical posttranslational modification influencing cancer pathogenesis.
• Palmitoyltransferase (DHHC) enzymes play a significant role in cancer development.
• Targeting DHHC offers a potential therapeutic strategy for malignant tumors.

Purpose of the Study:

• To design and synthesize novel DHHC inhibitors based on the phosphate-adenosine-5'-diphosphate (PAP) ligand.
• To evaluate the anticancer potential of synthesized pyrazolo[3,4-d]pyrimidine derivatives.
• To investigate the mechanism of action of the most potent compound.

Main Methods:

• Synthesis of pyrazolo[3,4-d]pyrimidine derivatives.
• In vitro assays for antiproliferative, migration, invasion, and apoptosis.
• Cell cycle analysis (G0/G1 arrest).
• Molecular docking and molecular dynamics simulations.

Main Results:

• Compound C9 demonstrated superior DHHC inhibitory activity and potent antiproliferative effects against MC38 cells with low toxicity.
• C9 effectively inhibited cancer cell migration and invasion, promoted apoptosis, and induced G0/G1 cell cycle arrest.
• Molecular modeling confirmed C9's stable binding to the DHHC active site.

Conclusions:

• Compound C9 is a promising novel DHHC inhibitor with significant anticancer properties.
• C9 warrants further investigation as a potential therapeutic agent for cancer treatment.
• Targeting protein palmitoylation via DHHC inhibition is a viable strategy in oncology.