Macrocyclization of Quinazoline-Based EGFR Inhibitors Leads to Exclusive Mutant Selectivity for EGFR L858R and Del19

Activating mutations in the epidermal growth factor receptor
(EGFR)
are frequent oncogenic drivers of non-small-cell lung cancer (NSCLC).
The most frequent alterations in EGFR are short in-frame deletions
in exon 19 (Del19) and the missense mutation L858R, which both lead
to increased activity and sensitization of NSCLC to EGFR inhibition.
The first approved EGFR inhibitors used for first-line treatment of
NSCLC, gefitinib and erlotinib, are quinazoline-based. However, both
inhibitors have several known off-targets, and they also potently
inhibit wild-type (WT) EGFR, resulting in side effects. Here, we applied
a macrocyclic strategy on a quinazoline-based scaffold as a proof-of-concept
study with the goal of increasing kinome-wide selectivity of this
privileged inhibitor scaffold. Kinome-wide screens and SAR studies
yielded 3f, a potent inhibitor for the most common EGFR
mutation (EGFR Del19: 119 nM) with selectivity against the WT receptor
(EGFR: >10 μM) and the kinome.