Structure-Guided Development of Covalent and Mutant-Selective Pyrazolopyrimidines to Target T790M Drug Resistance in Epidermal Growth Factor Receptor

Reversible
epidermal growth factor receptor (EGFR) inhibitors prompt a beneficial
clinical response in non-small cell lung cancer patients who harbor
activating mutations in EGFR. However, resistance mutations, particularly
the gatekeeper mutation T790M, limit this efficacy. Here, we describe
a structure-guided development of a series of covalent and mutant-selective
EGFR inhibitors that effectively target the T790M mutant. The pyrazolopyrimidine-based
core differs structurally from that of aminopyrimidine-based third-generation
EGFR inhibitors and therefore constitutes a new set of inhibitors
that target this mechanism of drug resistance. These inhibitors exhibited
strong inhibitory effects toward EGFR kinase activity and excellent
inhibition of cell growth in the drug-resistant cell line H1975, without
significantly affecting EGFR wild-type cell lines. Additionally, we
present the in vitro ADME/DMPK parameters for a subset of the inhibitors
as well as in vivo pharmacokinetics in mice for a candidate with promising
activity profile.