Mutant epidermal growth factor receptor (EGFR) is a major driver of non-small cell lung cancer (NSCLC). Marketed first generation inhibitors, such as erlotinib, effect a transient beneficial response in EGFR-mutant NSCLC patients before resistance mechanisms render these inhibitors ineffective. Secondary oncogenic EGFR mutations account for approximately 50% of relapses, the most common being the gatekeeper T790M substitution that renders existing therapies ineffective. The discovery of clinical candidate <b>PF-06747775 </b>is presented, which provides potent EGFR activity against the four common mutants (exon 19 deletion, L858R, and double mutants T790M/L858R and T790M/Del), selectivity over wild-type EGFR, and desirable ADME properties.

From HTS lead to clinic: Discovery of PF-06747775. A high affinity irreversible inhibitor targeting oncogenic EGFR mutants with selectivity over wild-type EGFR

256th National Meeting (2018)

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