Inhibitors targeting the activating mutants of the epidermal growth factor receptor (EGFR) have found success in the treatment of EGFR-mutant positive non-small cell lung cancer. A secondary point mutation (T790M) in the inhibitor binding site has been linked to the acquired resistance against the first generation therapeutics. Recently, a number of inhibitors designed to covalently inhibit both the activating and T790M resistance EGFR mutants have been reported to be effective in the clinic. Unfortunately, cases of a cysteine-to-serine (C797S) point mutation that conferred resistance to those covalent inhibitors have emerged. In this presentation, we describe the lead optimization of a series of noncovalent, pan-mutant selective EGFR inhibitors that should complement the covalent EGFR inhibitors. Using a noncovalent T790M resistant mutant selective EGFR inhibitor as a starting point, activities against the activating mutants (L858R and del746-750) were introduced through a series of structure-guided modifications to give a set of novel, pan-mutant inhibitors. The in vitro ADME-PK properties of the lead molecules were further optimized through a number of rational structural changes. The resulting inhibitor exhibited excellent cellular activity against both the activating (L858R and del746-750) and resistance mutants (T790M/L858R and T790M/del746-750) of EGFR, demonstrated target engagement in vivo and ADME-PK properties that are suitable for further evaluation.

Discovery of a noncovalent, mutant-selective epidermal growth factor receptor inhibitor

253rd National Meeting (2017)

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