Discovery of a Noncovalent, Mutant-Selective Epidermal Growth Factor Receptor Inhibitor

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 those first generation therapeutics. Herein, we
describe the lead optimization of a series of reversible, pan-mutant
(L858R, del746–750, T790M/L858R, and T790M/del746–750) EGFR inhibitors. By use of a noncovalent double
mutant (T790M/L858R and T790M/del746–750) selective
EGFR inhibitor (2) as a starting point, activities against
the single mutants (L858R and del746–750) were introduced
through a series of structure-guided modifications. The in vitro ADME-PK
properties of the lead molecules were further optimized through a
number of rational structural changes. The resulting inhibitor (21) exhibited excellent cellular activity against both the
single and double mutants of EGFR, demonstrating target engagement
in vivo and ADME-PK properties that are suitable for further evaluation.
The reversible, noncovalent inhibitors described complement the covalent
pan-mutant EGFR inhibitors that have shown encouraging results in
recent clinical trials.