Optimization of the 4-anilinoquin(az)oline scaffold as epidermal growth factor receptor (EGFR) inhibitors for chordoma utilizing a toxicology profiling assay platform

The 4-anilinoquin(az)oline is a well-known kinase inhibitor scaffold incorporated in clinical inhibitors including gefitinib, erlotinib, afatinib, and lapatinib, all of which have previously demonstrated activity against chordoma cell lines in vitro. We screened a focused array of compounds based on the 4-anilinoquin(az)oline scaffold against both U-CH1 and the epidermal growth factor receptor (EGFR) inhibitor resistant U-CH2. To prioritize the hit compounds for further development, we screened the compound set in a multiparameter cell health toxicity assay. The de-risked compounds were then screened against a wider panel of patient derived cell lines and demonstrated low micromolar efficacy in cells. We also investigated the properties that gave rise to the toxophore markers, including the structural and electronic features, while optimizing for EGFR in-cell target engagement. These de-risked leads present a potential new therapeutic avenue for treatment of chordomas and new chemical tools and probe compound 45 (UNC-CA359) to interrogate EGFR mediated disease phenotypes.

Automated summary

The study screened a group of compounds based on a well-known kinase inhibitor scaffold and identified a set of potential therapeutic compounds for chordomas. These compounds showed significant inhibitory effects in both cell lines and patient derived cells, and the study also investigated the properties related to their toxicity, providing new chemical tools and probe compound for studying EGFR mediated disease phenotypes.