Small molecule inhibitors of the Epidermal Growth Factor Receptor (EGFR) tyrosine kinase such as gefitinib and erlotinib have been employed successfully in the treatment of non-small cell lung cancer (NSCLC) patients harboring an activating mutation (EGFRm+). However, resistance to these inhibitors in the form of additional mutations such as T790M, (mutation of the gatekeeper residue), is recognized as a clinical issue. This presentation will describe the discovery and evolution of one of our novel chemical series, leading ultimately to the identification of AZD9291, an orally bioavailable, covalent EGFR inhibitor of both the resistance (NCI-H1975, cell phosphorylation IC50 <0.025 uM) and activating mutations (PC9, cell phosphorylation IC50<0.025 uM) that spares inhibition of the wild type form of the receptor (A431, cell phosphorylation IC50>0.5 uM). Wild type EGFR inhibition is believed to drive the observed dose limiting toxicities (such as skin rash and diarrhea) for these first generation therapies in the clinic. New data will be presented for the first time including a broader description of the medicinal chemistry program that led to the identification of AZD9291. We shall also present previously undisclosed work on the identification of additional distinct chemical series and an update of recent data from ongoing AZD9291 Phase I clinical studies in NSCLC patients.

L858R/T790M Double Mutant (resistance) cell IC50 uM EGFRm+ Single Mutant (activating) cell IC50 uM EGFR Wild Type cell IC50 uM Aqueous solubility, (salt) (pH=6.8, ug/mL) L858R/T790M Double Mutant efficacy (% TGI at 5mpk PO QD for 14 days) 
<0.025 <0.025 >0.5 >490 119 
L858R/T790M Double Mutant (resistance) cell IC50 uM EGFRm+ Single Mutant (activating) cell IC50 uM EGFR Wild Type cell IC50 uM Aqueous solubility, (salt) (pH=6.8, ug/mL) L858R/T790M Double Mutant efficacy (% TGI at 5mpk PO QD for 14 days) 
<0.025 <0.025 >0.5 >490 119 

Citation Format: Richard A. Ward, Susan Ashton, Mark Anderton, Pete G. Ballard, Rob H. Bradbury, Sam Butterworth, Nicola Colclough, Darren A E Cross, M Ray V. Finlay, Heather L. McFarland, Martine Mellor, Mike J. Waring. Structure-based development of covalent inhibitors of the activating and T790M gatekeeper mutant forms of the epidermal growth factor receptor (EGFR) leading to the discovery of AZD9291. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4744. doi:10.1158/1538-7445.AM2014-4744