Design and evaluation of novel 4-anilinoquinolines and quinazolines as EGFR inhibitors in lung cancer and chordoma

Asquith, C. R. M.; Maffuid, K. A.; Laitinen, T.; Torrice, C. D.; Tizzard, G. J.; Alamillo-Ferrer, C.; Koshlap, K. M.; Crona, D. J.; Zuercher, W.

doi:10.1101/545525

bioRxiv · 10.1101/545525

Design and evaluation of novel 4-anilinoquinolines and quinazolines as EGFR inhibitors in lung cancer and chordoma

Asquith, C. R. M.·Maffuid, K. A.·Laitinen, T.·Torrice, C. D.·Tizzard, G. J.·Alamillo-Ferrer, C.·Koshlap, K. M.·Crona, D. J.·Zuercher, W.

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Abstract

Epidermal growth factor receptor (EGFR) inhibitors have been used to target non-small cell lung cancer (NSCLC) and chordomas with varying amounts of success. We have probed several key structural features including an interaction with Asp855 within the EGFR DGF motif and interactions with the active site water network. The EGFR target engagement was then evaluated in an in-cell assay. Additionally, inhibitors were profiled in representative cellular models of NSCLC and chordomas. In addition to a structure activity relationship insights for EGFR inhibtior design, we also identified a compound (18) that is the most potent inhibitor (IC50 = 310 nM) on the UCH-2 chordoma cell line to date.

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Asquith, C. R. M., Maffuid, K. A., Laitinen, T., Torrice, C. D., Tizzard, G. J., Alamillo-Ferrer, C., Koshlap, K. M., Crona, D. J., Zuercher, W.. 2019-02-11. Design and evaluation of novel 4-anilinoquinolines and quinazolines as EGFR inhibitors in lung cancer and chordoma. https://doi.org/10.1101/545525

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