The EGFR T790M gatekeeper mutation is the predominant mechanism of acquired resistance to EGFR TKIs used to treat patients with EGFR-mutant NSCLC. Acquisition of this second mutation confers resistance by rendering the kinase less sensitive to first generation (reversible) and second generation (irreversible) EGFR inhibitors. It has been proposed that higher dosing of these agents to modulate the T790M mutant may be effective, however the exceptional potency of these agents against EGFR WT causes dose limiting toxicity in the form of severe skin rash and diarrhea.<br/><br/>We present here the discovery and development of a 7H-pyrrolo[2,3-d]pyrimidine series from initial leads to the culmination of PF-06459988. The primary objectives of this effort were to develop irreversible inhibitors that provided i) high selectivity for T790M mutants over EGFR WT, ii) high binding affinity for T790M and iii) the ability to utilize warheads with low intrinsic reactivity to mitigate potential off-target binding.

Discovery and development of a series of irreversible EGFR_T790M 7H-pyrrolo[2,3-d]pyrimidine inhibitors with high selectivity over EGFR wild type

249th National Meeting (2015)

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