1 research outputs found
Discovery of <i>N</i>‑((3<i>R</i>,4<i>R</i>)‑4-Fluoro-1-(6-((3-methoxy-1-methyl‑1<i>H</i>‑pyrazol-4-yl)amino)-9-methyl‑9<i>H</i>‑purin-2-yl)pyrrolidine-3-yl)acrylamide (PF-06747775) through Structure-Based Drug Design: A High Affinity Irreversible Inhibitor Targeting Oncogenic EGFR Mutants with Selectivity over Wild-Type EGFR
Mutant epidermal growth factor receptor
(EGFR) is a major driver
of non-small-cell lung cancer (NSCLC). Marketed first generation inhibitors,
such as erlotinib, effect a transient beneficial response in EGFR
mutant NSCLC patients before resistance mechanisms render these inhibitors
ineffective. Secondary oncogenic EGFR mutations account for approximately
50% of relapses, the most common being the gatekeeper T790M substitution
that renders existing therapies ineffective. The discovery of PF-06459988
(<b>1</b>), an irreversible pyrrolopyrimidine inhibitor of EGFR
T790M mutants, was recently disclosed. Herein, we describe our continued efforts to achieve potency across
EGFR oncogenic mutations and improved kinome selectivity, resulting
in the discovery of clinical candidate PF-06747775 (<b>21</b>), which provides potent EGFR activity against the four common mutants
(exon 19 deletion (Del), L858R, and double mutants T790M/L858R and
T790M/Del), selectivity over wild-type EGFR, and desirable ADME properties.
Compound <b>21</b> is currently being evaluated in phase-I clinical
trials of mutant EGFR driven NSCLC