Targeting Her2-insYVMA with Covalent Inhibitors-A Focused Compound Screening and Structure-Based Design Approach

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Human Epidermal growth factor Receptor 2 (Her2) mutations or amplification drive non-small cell lung cancer (NSCLC).
• Her2 also mediates resistance to epidermal growth factor receptor (EGFR) inhibitors.
• Currently, no Her2-targeting small-molecule inhibitors are approved for clinical use in NSCLC.

Purpose of the Study:

• To develop novel small-molecule inhibitors targeting Her2 for clinical application.
• To address the unmet need for Her2-targeted therapies in NSCLC.

Main Methods:

• Modification of the pyrrolopyrimidine scaffold using structural motifs from a large-scale screening campaign (>1600 compounds).
• Design of covalent inhibitors targeting a reactive cysteine in the Her2 binding site.
• Structure-based drug design and optimization using complex crystal structures.
• Analysis of binding kinetics, ADME properties, mass spectrometry, and western blot.

Main Results:

• Novel pyrrolopyrimidine-based inhibitors targeting wild-type and mutant Her2 (Her2-A775_G776insYVMA) were synthesized.
• Inhibitors were designed for covalent binding to a specific cysteine residue in the Her2 active site.
• Structure-based drug design and experimental validation (kinetics, ADME, MS, WB) supported the efficacy of the developed inhibitors.

Conclusions:

• The study successfully developed novel covalent small-molecule inhibitors targeting Her2.
• These inhibitors demonstrate potential as a new therapeutic strategy for NSCLC driven by Her2 alterations.
• The findings provide a foundation for further clinical development of these Her2-targeting agents.