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

Mutated or amplified
Her2 serves as a driver of non-small cell
lung cancer or mediates resistance toward the inhibition of its family
member epidermal growth factor receptor with small-molecule inhibitors.
To date, small-molecule inhibitors targeting Her2 which can be used
in clinical routine are lacking, and therefore, the development of
novel inhibitors was undertaken. In this study, the well-established
pyrrolopyrimidine scaffold was modified with structural motifs identified
from a screening campaign with more than 1600 compounds, which were
applied against wild-type Her2 and its mutant variant Her2-A775_G776insYVMA.
The resulting inhibitors were designed to covalently target a reactive
cysteine in the binding site of Her2 and were further optimized by
means of structure-based drug design utilizing a set of obtained complex
crystal structures. In addition, the analysis of binding kinetics
and absorption, distribution, metabolism, and excretion parameters
as well as mass spectrometry experiments and western blot analysis
substantiated our approach.