Structure-Based Approach
for the Discovery of Pyrrolo[3,2‑<i>d</i>]pyrimidine-Based
EGFR T790M/L858R Mutant Inhibitors
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Abstract
The epidermal growth factor receptor (EGFR) family plays
a critical
role in vital cellular processes and in various cancers. Known EGFR
inhibitors exhibit distinct antitumor responses against the various
EGFR mutants associated with nonsmall-cell lung cancer. The L858R
mutation enhances clinical sensitivity to gefitinib and erlotinib
as compared with wild type and reduces the relative sensitivity to
lapatinib. In contrast, the T790M mutation confers drug resistance
to gefitinib and erlotinib. We determined crystal structures of the
wild-type and T790M/L858R double mutant EGFR kinases with reversible
and irreversible pyrrolo[3,2-<i>d</i>]pyrimidine inhibitors
based on analogues of TAK-285 and neratinib. In these structures,
M790 adopts distinct conformations to accommodate different inhibitors,
whereas R858 allows conformational variations of the activation loop.
These results provide structural insights for understanding the structure–activity
relationships that should contribute to the development of potent
inhibitors against drug-sensitive or -resistant EGFR mutations