1 research outputs found
Discovery of 1‑{(3<i>R</i>,4<i>R</i>)‑3-[({5-Chloro-2-[(1-methyl‑1<i>H</i>‑pyrazol-4-yl)amino]‑7<i>H</i>‑pyrrolo[2,3‑<i>d</i>]pyrimidin-4-yl}oxy)methyl]-4-methoxypyrrolidin-1-yl}prop-2-en-1-one (PF-06459988), a Potent, WT Sparing, Irreversible Inhibitor of T790M-Containing EGFR Mutants
First
generation EGFR TKIs (gefitinib, erlotinib) provide significant
clinical benefit for NSCLC cancer patients with oncogenic EGFR mutations.
Ultimately, these patients’ disease progresses, often driven
by a second-site mutation in the EGFR kinase domain (T790M). Another
liability of the first generation drugs is severe adverse events driven
by inhibition of WT EGFR. As such, our goal was to develop a highly
potent irreversible inhibitor with the largest selectivity ratio between
the drug-resistant double mutants (L858R/T790M, Del/T790M) and WT
EGFR. A unique approach to develop covalent inhibitors, optimization
of <i>reversible binding affinity</i>, served as a cornerstone
of this effort. PF-06459988 was discovered as a novel, third generation
irreversible inhibitor, which demonstrates (i) high potency and specificity
to the T790M-containing double mutant EGFRs, (ii) minimal intrinsic
chemical reactivity of the electrophilic warhead, (iii) greatly reduced
proteome reactivity relative to earlier irreversible EGFR inhibitors,
and (iv) minimal activity against WT EGFR