Discovery Of A Potent Covalent Mutant-Selective Egfr Inhibitor - The Journey From High Throughput Screening To Egf816

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PAEpidermal growth factor receptor (EGFR) is a validated therapeutic target for lung cancer. First and second generation EGFR inhibitors (e.g., gefitinib, erlotinib and afatinib) have revolutionized treatment paradigms of non-small cell lung cancer (NSCLC) patients with oncogenic EGFR mutations. The use of EGFR tyrosine kinase inhibitors (TKI) provides superior efficacy compared to chemotherapy in patients with EGFR L858R or exon 19 deletion tumors. However, resistance inevitably develops after 8-12 months of treatment; most commonly via a secondary T790M point mutation at the gatekeeper residue of EGFR. Furthermore, responses are hindered due to treatment intolerance in the form of rash and diarrhea that are mediated by simultaneous inhibition of wild-type (WT) EGFR at doses required for mutant EGFR suppression. To overcome these limitations, we initiated a project to identify mutant-selective EGFR inhibitors that potently inhibit both activating and T790M resistance EGFR mutations while sparing WT EGFR.In this presentation, we report our medicinal chemistry approach and optimization that led to the discovery of EGF816, a selective and potent covalent mutant-selective EGFR inhibitor with single digit nanomolar cellular target modulation on both activating and T790M resistance mutations. In addition, we will also report validated clinical efficacy data from the first patient treated with EGF816.Citation Format: Gerald Lelais, Robert Epple, Pierre-Yves Michellys, Thomas H. Marsilje, Yun Long, Matthew McNeill, Bei Chen, Wenshuo Lu, Badry Bursulaya, Michael DiDonato, Yong Jia, Shailaja Kasibhatla, Chun Li, Igor Matushansky, Steven Bender. Discovery of a potent covalent mutant-selective EGFR inhibitor - the journey from high throughput screening to EGF816. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2585. doi:10.1158/1538-7445.AM2015-2585