The EGFR T790M gatekeeper mutation is the predominant mechanism of acquired resistance to current EGFR TKIs used to treat patients with EGFR-mutant NSCLC. In <i>ca</i>: 60 % of patients who initially respond but then become resistant to first generation reversible inhibitors, acquisition of this second mutation confers resistance by rendering the kinase insensitive to the current first generation reversible and second generation irreversible inhibitors. In addition, current EGFR TKIs are potent inhibitors of EGFR wild type, causing dose-limiting toxicity in the form of skin rash and diarrhea.<br/><br/>We present here the discovery and development of a novel series that shows activity against the T790M gatekeeper mutation in addition to the single activating mutations Del and L858R, whilst retaining selectivity over EGFR wild type. This discovery effort culminated in the advancement of the clinical candidate which will be disclosed in the presentation.

Discovery of a next generation irreversible inhibitor targeting the resistance mutation T790M and activating mutations in NSCLC with a broad selectivity margin over EGFR wild type

249th National Meeting (2015)

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