Targeting the Grb2 cSH3 domain: Design, synthesis and biological evaluation of the first series of modulators

Area of Science:

• Biochemistry and Molecular Biology
• Medicinal Chemistry
• Oncology

Background:

• Growth factor receptor bound protein 2 (Grb2) is a key adaptor protein regulating cellular pathways.
• Dysregulation of Grb2 contributes to oncogenesis and its overexpression is observed in various cancers.
• Grb2 represents a promising therapeutic target for novel anticancer drug development.

Purpose of the Study:

• To synthesize and biologically evaluate a new series of Grb2 inhibitors.
• To identify potent Grb2 inhibitors with anticancer activity.
• To establish an early structure-activity relationship for Grb2 inhibitors.

Main Methods:

• Synthesis of novel Grb2 inhibitor derivatives.
• Kinetic binding experiments to assess protein-ligand interactions.
• In vitro evaluation in a panel of cancer cell lines.
• Metabolic stability and reactive oxygen species (ROS) production assays.
• Molecular docking studies.

Main Results:

• Five newly synthesized derivatives demonstrated Grb2 binding with inhibitory concentrations in the low micromolar range.
• Derivative 12 exhibited significant inhibitory activity, with an IC50 of approximately 6 μM against glioblastoma and ovarian cancer cells, and 1.67 μM against lung cancer cells.
• Metabolic stability and ROS production of derivative 12 were evaluated.
• Structure-activity relationships were rationalized based on biological data and docking studies.

Conclusions:

• The developed Grb2 inhibitors show potential for anticancer drug development.
• Derivative 12 is a highly promising lead compound for further investigation.
• The study provides insights into structure-activity relationships for Grb2 inhibition.