Start Selective and Rigidify: The Discovery Path toward a Next Generation of EGFR Tyrosine Kinase Inhibitors

The epidermal growth factor receptor (EGFR), when carrying
an activating
mutation like del19 or L858R, acts as an oncogenic driver in a subset
of lung tumors. While tumor responses to tyrosine kinase inhibitors
(TKIs) are accompanied by marked tumor shrinkage, the response is
usually not durable. Most patients relapse within two years of therapy
often due to acquisition of an additional mutation in EGFR kinase
domain that confers resistance to TKIs. Crucially, oncogenic EGFR
harboring both resistance mutations, T790M and C797S, can no longer
be inhibited by currently approved EGFR TKIs. Here, we describe the
discovery of BI-4020, which is a noncovalent, wild-type
EGFR sparing, macrocyclic TKI. BI-4020 potently inhibits
the above-described EGFR variants and induces tumor regressions in
a cross-resistant EGFRdel19 T790M C797S xenograft
model. Key was the identification of a highly selective but moderately
potent benzimidazole followed by complete rigidification of the molecule
through macrocyclization.